Transporters and ion channels

ABSTRACT

The invention provides human transporters and ion channels (TRICH) and polynucleotides which identify and encode TRICH. The invention also provides expression vectors, host cells, antibodies, agonists, and antagonists. The invention also provides methods for diagnosing, treating, or preventing disorders associated with aberrant expression of TRICH.

TECHNICAL FIELD

[0001] This invention relates to nucleic acid and amino acid sequencesof transporters and ion channels and to the use of these sequences inthe diagnosis, treatment, and prevention of transport, neurological,muscle, immunological, and cell proliferative disorders, and in theassessment of the effects of exogenous compounds on the expression ofnucleic acid and amino acid sequences of transporters and ion channels.

BACKGROUND OF THE INVENTION

[0002] Eukaryotic cells are surrounded and subdivided into functionallydistinct organelles by hydrophobic lipid bilayer membranes which arehighly impermeable to most polar molecules. Cells and organelles requiretransport proteins to import and export essential nutrients and metalions including K⁺, NH₄ ⁺, P_(i), SO₄ ²⁻, sugars, and vitamins, as wellas various metabolic waste products. Transport proteins also play rolesin antibiotic resistance, toxin secretion, ion balance, synapticneurotransmission, kidney function, intestinal absorption, tumor growth,and other diverse cell functions (Griffith, J. and C. Sansom (1998) TheTransporter Facts Book Academic Press, San Diego Calif., pp. 3-29).Transport can occur by a passive concentration-dependent mechanism, orcan be linked to an energy source such as ATP hydrolysis or an iongradient. Proteins that function in transport include carrier proteins,which bind to a specific solute and undergo a conformational change thattranslocates the bound solute across the membrane, and channel proteins,which form hydrophilic pores that allow specific solutes to diffusethrough the membrane down an electrochemical solute gradient.

[0003] Carrier proteins which transport a single solute from one side ofthe membrane to the other are called uniporters. In contrast, coupledtransporters link the transfer of one solute with simultaneous orsequential transfer of a second solute, either in the same direction(symport) or in the opposite direction (antiport). For example,intestinal and kidney epithelium contains a variety of symporter systemsdriven by the sodium gradient that exists across the plasma membrane.Sodium moves into the cell down its electrochemical gradient and bringsthe solute into the cell with it. The sodium gradient that provides thedriving force for solute uptake is maintained by the ubiquitous Na⁺/K⁺ATPase system. Sodium-coupled transporters include the mammalian glucosetransporter (SGLT1), iodide transporter (NIS), and multivitamintransporter (SMVT). All three transporters have twelve putativetransmembrane segments, extracellular glycosylation sites, andcytoplasmically-oriented N- and C-termini. NIS plays a crucial role inthe evaluation, diagnosis, and treatment of various thyroid pathologiesbecause it is the molecular basis for radioiodide thyroid-imagingtechniques and for specific targeting of radioisotopes to the thyroidgland (Levy, O. et al. (1997) Proc. Natl. Acad. Sci. USA 94:5568-5573).SMVT is expressed in the intestinal mucosa, kidney, and placenta, and isimplicated in the transport of the water-soluble vitamins, e.g., biotinand pantothenate (Prasad, P. D. et al. (1998) J. Biol. Chem.273:7501-7506).

[0004] One of the largest families of transporters is the majorfacilitator superfamily (MFS), also called theuniporter-symporter-antiporter family. MFS transporters are singlepolypeptide carriers that transport small solutes in response to iongradients. Members of the MFS are found in all classes of livingorganisms, and include transporters for sugars, oligosaccharides,phosphates, nitrates, nucleosides, monocarboxylates, and drugs. MFStransporters found in eukaryotes all have a structure comprising 12transmembrane segments (Pao, S. S. et al. (1998) Microbiol. Molec. Biol.Rev. 62:1-34). The largest family of MFS transporters is the sugartransporter family, which includes the seven glucose transporters(GLUT1-GLUT7) found in humans that are required for the transport ofglucose and other hexose sugars. These glucose transport proteins haveunique tissue distributions and physiological functions. GLUT1 providesmany cell types with their basal glucose requirements and transportsglucose across epithelial and endothelial barrier tissues; GLUT2facilitates glucose uptake or efflux from the liver; GLUT3 regulatesglucose supply to neurons; GLUT4 is responsible for insulin-regulatedglucose disposal; and GLUT5 regulates fructose uptake into skeletalmuscle. Defects in glucose transporters are involved in a recentlyidentified neurological syndrome causing infantile seizures anddevelopmental delay, as well as glycogen storage disease, Fanconi-Bickelsyndrome, and non-insulin-dependent diabetes mellitus (Mueckler, M.(1994) Eur. J. Biochem. 219:713-725; Longo, N. and L. J. Elsas (1998)Adv. Pediatr. 45:293-313).

[0005] Monocarboxylate anion transporters are proton-coupled symporterswith a broad substrate specificity that includes L-lactate, pyruvate,and the ketone bodies acetate, acetoacetate, and beta-hydroxybutyrate.At least seven isoforms have been identified to date. The isoforms arepredicted to have twelve transmembrane (TM) helical domains with a largeintracellular loop between TM6 and TM7, and play a critical role inmaintaining intracellular pH by removing the protons that are producedstoichiometrically with lactate during glycolysis. The bestcharacterized H⁺-monocarboxylate transporter is that of the erythrocytemembrane, which transports L-lactate and a wide range of other aliphaticmonocarboxylates. Other cells possess H⁺-linked monocarboxylatetransporters with differing substrate and inhibitor selectivities. Inparticular, cardiac muscle and tumor cells have transporters that differin their K_(m) values for certain substrates, includingstereoselectivity for L- over D-lactate, and in their sensitivity toinhibitors. There are Na⁺-monocarboxylate cotransporters on the luminalsurface of intestinal and kidney epithelia, which allow the uptake oflactate, pyruvate, and ketone bodies in these tissues. In addition,there are specific and selective transporters for organic cations andorganic anions in organs including the kidney, intestine and liver.Organic anion transporters are selective for hydrophobic, chargedmolecules with electron-attracting side groups. Organic cationtransporters, such as the ammonium transporter, mediate the secretion ofa variety of drugs and endogenous metabolites, and contribute to themaintenance of intercellular pH (Poole, R. C. and A. P. Halestrap (1993)Am. J. Physiol. 264:C761-C782; Price, N. T. et al. (1998) Biochem. J.329:321-328; and Martinelle, K. and I. Haggstrom (1993) J. Biotechnol.30:339-350).

[0006] Recently, Yamashita et al. (Yamashita, T. et al. (1997) J. Biol.Chem. 272:10205-10211) have identified a peptide/histidine transporter(PHT1) in rat, expressed particularly in brain and retina tissue. Whenexpressed in Xenopus oocytes, PHT1 induces proton-dependent histidinetransport. This transport process was inhibited by dipeptides andtripeptides but not free amino acids such as glutamate, glycine,leucine, methionine, and aspartate. This transporter is believed to be amember of a superfamily of proton-coupled peptide and nitratetransporters.

[0007] ATP-binding cassette (ABC) transporters are members of asuperfamily of membrane proteins that transport substances ranging fromsmall molecules such as ions, sugars, amino acids, peptides, andphospholipids, to lipopeptides, large proteins, and complex hydrophobicdrugs. ABC transporters consist of four modules: two nucleotide-bindingdomains (NBD), which hydrolyze ATP to supply the energy required fortransport, and two membrane-spanning domains (MSD), each containing sixputative transmembrane segments. These four modules may be encoded by asingle gene, as is the case for the cystic fibrosis transmembraneregulator (CFTR), or by separate genes. When encoded by separate genes,each gene product contains a single NBD and MSD. These “half-molecules”form homo- and heterodimers, such as Tap1 and Tap2, the endoplasmicreticulum-based major histocompatibility (MHC) peptide transport system.Several genetic diseases are attributed to defects in ABC transporters,such as the following diseases and their corresponding proteins: cysticfibrosis (CFTR, an ion channel), adrenoleukodystrophy(adrenoleukodystrophy protein, ALDP), Zellweger syndrome (peroxisomalmembrane protein-70, PMP70), and hyperinsulinemic hypoglycemia(sulfonylurea receptor, SUR). Overexpression of the multidrug resistance(MDR) protein, another ABC transporter, in human cancer cells makes thecells resistant to a variety of cytotoxic drugs used in chemotherapy(Taglicht, D. and S. Michaelis (1998) Meth. Enzymol. 292:130-162).

[0008] A number of metal ions such as iron, zinc, copper, cobalt,manganese, molybdenum, selenium, nickel, and chromium are important ascofactors for a number of enzymes. For example, copper is involved inhemoglobin synthesis, connective tissue metabolism, and bonedevelopment, by acting as a cofactor in oxidoreductases such assuperoxide dismutase, ferroxidase (ceruloplasmin), and lysyl oxidase.Copper and other metal ions must be provided in the diet, and areabsorbed by transporters in the gastrointestinal tract. Plasma proteinstransport the metal ions to the liver and other target organs, wherespecific transporters move the ions into cells and cellular organellesas needed. Imbalances in metal ion metabolism have been associated witha number of disease states (Danks, D. M. (1986) J. Med. Genet.23:99-106).

[0009] Transport of fatty acids across the plasma membrane can occur bydiffusion, a high capacity, low affinity process. However, under normalphysiological conditions a significant fraction of fatty acid transportappears to occur via a high affinity, low capacity protein-mediatedtransport process. Fatty acid transport protein (FATP), an integralmembrane protein with four transmembrane segments, is expressed intissues exhibiting high levels of plasma membrane fatty acid flux, suchas muscle, heart, and adipose. Expression of FATP is upregulated in3T3-L1 cells during adipose conversion, and expression in COS7fibroblasts elevates uptake of long-chain fatty acids (Hui, T. Y. et al.(1998) J. Biol. Chem. 273:27420-27429).

[0010] Mitochondrial carrier proteins are transmembrane-spanningproteins which transport ions and charged metabolites between thecytosol and the mitochondrial matrix. Examples include the ADP, ATPcarrier protein; the 2-oxoglutarate/malate carrier; the phosphatecarrier protein; the pyruvate carrier; the dicarboxylate carrier whichtransports malate, succinate, fumarate, and phosphate; thetricarboxylate carrier which transports citrate and malate; and theGrave's disease carrier protein, a protein recognized by IgG in patientswith active Grave's disease, an autoimmune disorder resulting inhyperthyroidism. Proteins in this family consist of three tandem repeatsof an approximately 100 amino acid domain, each of which contains twotransmembrane regions (Stryer, L. (1995) Biochemistry, W. H. Freeman andCompany, New York N.Y., p. 551; PROSITE PDOC00189 Mitochondrial energytransfer proteins signature; Online Mendelian Inheritance in Man (OMIM)*275000 Graves Disease).

[0011] This class of transporters also includes the mitochondrialuncoupling proteins, which create proton leaks across the innermitochondrial membrane, thus uncoupling oxidative phosphorylation fromATP synthesis. The result is energy dissipation in the form of heatMitochondrial uncoupling proteins have been implicated as modulators ofthermoregulation and metabolic rate, and have been proposed as potentialtargets for drugs against metabolic diseases such as obesity (Ricquier,D. et al. (1999) J. Int. Med. 245:637-642).

[0012] Ion Channels

[0013] The electrical potential of a cell is generated and maintained bycontrolling the movement of ions across the plasma membrane. Themovement of ions requires ion channels, which form ion-selective poreswithin the membrane. There are two basic types of ion channels, iontransporters and gated ion channels. Ion transporters utilize the energyobtained from ATP hydrolysis to actively transport an ion against theion's concentration gradient. Gated ion channels allow passive flow ofan ion down the ion's electrochemical gradient under restrictedconditions. Together, these types of ion channels generate, maintain,and utilize an electrochemical gradient that is used in 1) electricalimpulse conduction down the axon of a nerve cell, 2) transport ofmolecules into cells against concentration gradients, 3) initiation ofmuscle contraction, and 4) endocrine cell secretion.

[0014] Ion Transporters.

[0015] Ion transporters generate and maintain the resting electricalpotential of a cell. Utilizing the energy derived from ATP hydrolysis,they transport ions against the ion's concentration gradient. Thesetransmembrane ATPases are divided into three families. Thephosphorylated (P) class ion transporters, including Na⁺—K⁺ ATPase,Ca²⁺-ATPase, and H⁺-ATPase, are activated by a phosphorylation event.P-class ion transporters are responsible for maintaining restingpotential distributions such that cytosolic concentrations of Na⁺ andCa²⁺ are low and cytosolic concentration of K⁺ is high. The vacuolar (V)class of ion transporters includes H⁺ pumps on intracellular organelles,such as lysosomes and Golgi. V-class ion transporters are responsiblefor generating the low pH within the lumen of these organelles that isrequired for function. The coupling factor (F) class consists of H⁺pumps in the mitochondria. F-class ion transporters utilize a protongradient to generate ATP from ADP and inorganic phosphate (P_(i)).

[0016] The P-ATPases are hexamers of a 100 kD subunit with tentransmembrane domains and several large cytoplasmic regions that mayplay a role in ion binding (Scarborough, G. A. (1999) Curr. Opin. CellBiol. 11:517-522). The V-ATPases are composed of two functional domains:the V₁ domain, a peripheral complex responsible for ATP hydrolysis; andthe V₀ domain, an integral complex responsible for proton translocationacross the membrane. The F-ATPases are structurally and evolutionarilyrelated to the V-ATPases. The F-ATPase F₀ domain contains 12 copies ofthe c subunit, a highly hydrophobic protein composed of twotransmembrane domains and containing a single buried carboxyl group inTM2 that is essential for proton transport. The V-ATPase V₀ domaincontains three types of homologous c subunits with four or fivetransmembrane domains and the essential carboxyl group in TM4 or TM3.Both types of complex also contain a single a subunit that may beinvolved in regulating the pH dependence of activity (Forgac, M. (1999)J. Biol. Chem. 274:12951-12954).

[0017] The resting potential of the cell is utilized in many processesinvolving carrier proteins and gated ion channels. Carrier proteinsutilize the resting potential to transport molecules into and out of thecell. Amino acid and glucose transport into many cells is linked tosodium ion co-transport (symport) so that the movement of Na⁺ down anelectrochemical gradient drives transport of the other molecule up aconcentration gradient. Similarly, cardiac muscle links transfer of Ca²⁺out of the cell with transport of Na⁺ into the cell (antiport).

[0018] Gated Ion Channels

[0019] Gated ion channels control ion flow by regulating the opening andclosing of pores. The ability to control ion flux through various gatingmechanisms allows ion channels to mediate such diverse signaling andhomeostatic functions as neuronal and endocrine signaling, musclecontraction, fertilization, and regulation of ion and pH balance. Gatedion channels are categorized according to the manner of regulating thegating function. Mechanically-gated channels open their pores inresponse to mechanical stress; voltage-gated channels (e.g., Na⁺, K⁺,Ca²⁺, and Cl⁻ channels) open their pores in response to changes inmembrane potential; and ligand-gated channels (e.g., acetylcholine-,serotonin-, and glutamate-gated cation channels, and GABA- andglycine-gated chloride channels) open their pores in the presence of aspecific ion, nucleotide, or neurotransmitter. The gating properties ofa particular ion channel (i.e., its threshold for and duration ofopening and closing) are sometimes modulated by association withauxiliary channel proteins and/or post translational modifications, suchas phosphorylation.

[0020] Mechanically-gated or mechanosensitive ion channels act astransducers for the senses of touch, hearing, and balance, and also playimportant roles in cell volume regulation, smooth muscle contraction,and cardiac rhythm generation. A stretch-inactivated channel (SIC) wasrecently cloned from rat kidney. The SIC channel belongs to a group ofchannels which are activated by pressure or stress on the cell membraneand conduct both Ca²⁺ and Na⁺ (Suzuki, M. et al. (1999) J. Biol. Chem.274:6330-6335).

[0021] The pore-forming subunits of the voltage-gated cation channelsform a superfamily of ion channel proteins. The characteristic domain ofthese channel proteins comprises six transmembrane domains (S1-S6), apore-forming region (P) located between S5 and S6, and intracellularamino and carboxy termini. In the Na⁺ and Ca²⁺ subfamilies, this domainis repeated four times, while in the K⁺ channel subfamily, each channelis formed from a tetramer of either identical or dissimilar subunits.The P region contains information specifying the ion selectivity for thechannel. In the case of K⁺ channels, a GYG tripeptide is involved inthis selectivity (Ishii, T. M. et al. (1997) Proc. Natl. Acad. Sci. USA94:11651-11656).

[0022] Voltage-gated Na⁺ and K⁺ channels are necessary for the functionof electrically excitable cells, such as nerve and muscle cells. Actionpotentials, which lead to neurotransmitter release and musclecontraction, arise from large, transient changes in the permeability ofthe membrane to Na⁺ and K⁺ ions. Depolarization of the membrane beyondthe threshold level opens voltage-gated Na⁺ channels. Sodium ions flowinto the cell, further depolarizing the membrane and opening morevoltage-gated Na⁺ channels, which propagates the depolarization down thelength of the cell. Depolarization also opens voltage-gated potassiumchannels. Consequently, potassium ions flow outward, which leads torepolarization of the membrane. Voltage-gated channels utilize chargedresidues in the fourth transmembrane segment (S4) to sense voltagechange. The open state lasts only about 1 millisecond, at which time thechannel spontaneously converts into an inactive state that cannot beopened irrespective of the membrane potential. Inactivation is mediatedby the channel's N-terminus, which acts as a plug that closes the pore.The transition from an inactive to a closed state requires a return toresting potential.

[0023] Voltage-gated Na⁺ channels are heterotrimeric complexes composedof a 260 kDa pore-forming a subunit that associates with two smallerauxiliary subunits, β1 and β2. The β2 subunit is a integral membraneglycoprotein that contains an extracellular Ig domain, and itsassociation with α and β1 subunits correlates with increased functionalexpression of the channel, a change in its gating properties, as well asan increase in whole cell capacitance due to an increase in membranesurface area (Isom, L. L. et al. (1995) Cell 83:433-442).

[0024] Non voltage-gated Na⁺ channels include the members of theamiloride-sensitive Na⁺ channel/degenerin (NaC/DEG) family. Channelsubunits of this family are thought to consist of two transmembranedomains flanking a long extracellular loop, with the amino and carboxyltermini located within the cell. The NaC/DEG family includes theepithelial Na⁺ channel (ENaC) involved in Na⁺ reabsorption in epitheliaincluding the airway, distal colon, cortical collecting duct of thekidney, and exocrine duct glands. Mutations in ENaC result inpseudohypoaldosteronism type 1 and Liddle's syndrome(pseudohyperaldosteronism). The NaC/DEG family also includes therecently characterized H⁺-gated cation channels or acid-sensing ionchannels (ASIC). ASIC subunits are expressed in the brain and formheteromultimeric Na⁺-permeable channels. These channels require acid pHfluctuations for activation ASIC subunits show homology to thedegenerins, a family of mechanically-gated channels originally isolatedfrom C. elegans. Mutations in the degenerins cause neurodegeneration.ASIC subunits may also have a role in neuronal function, or in painperception, since tissue acidosis causes pain (Waldmann, R. and M.Lazdunski (1998) Curr. Opin. Neurobiol. 8:418-424; Eglen, R. M. et al.(1999) Trends Pharmacol. Sci. 20:337-342).

[0025] K⁺ channels are located in all cell types, and may be regulatedby voltage, ATP concentration, or second messengers such as Ca²⁺ andcAMP. In non-excitable tissue, K⁺ channels are involved in proteinsynthesis, control of endocrine secretions, and the maintenance ofosmotic equilibrium across membranes. In neurons and other excitablecells, in addition to regulating action potentials and repolarizingmembranes, K⁺ channels are responsible for setting resting membranepotential. The cytosol contains non-diffusible anions and, to balancethis net negative charge, the cell contains a Na⁺-K⁺ pump and ionchannels that provide the redistribution of Na⁺, K⁺, and Cl⁻. The pumpactively transports Na⁺ out of the cell and K⁺ into the cell in a 3:2ratio. Ion channels in the plasma membrane allow K⁺ and Cl⁻ to flow bypassive diffusion. Because of the high negative charge within thecytosol, Cl⁻ flows out of the cell. The flow of K⁺ is balanced by anelectromotive force pulling K⁺ into the cell, and a K⁺ concentrationgradient pushing K⁺ out of the cell. Thus, the resting membranepotential is primarily regulated by K⁺ flow (Salkoff, L. and T. Jegla(1995) Neuron 15:489-492).

[0026] Potassium channel subunits of the Shaker-like superfamily allhave the characteristic six transmembrane/1 pore domain structure. Foursubunits combine as homo- or heterotetramers to form functional Kchannels. These pore-forming subunits also associate with variouscytoplasmic β subunits that alter channel inactivation kinetics. TheShaker-like channel family includes the voltage-gated K⁺ channels aswell as the delayed rectifier type channels such as the humanether-a-go-go related gene (HERG) associated with long QT, a cardiacdysrythmia syndrome (Curran, M. E. (1998) Curr. Opin. Biotechnol.9:565-572; Kaczorowski, G. J. and M. L. Garcia (1999) Curr. Opin. Chem.Biol. 3:448-458).

[0027] A second superfamily of K⁺ channels is composed of the inwardrectifying channels (Kir). Kir channels have the property ofpreferentially conducting K⁺ currents in the inward direction. Theseproteins consist of a single potassium selective pore domain and twotransmembrane domains, which correspond to the fifth and sixthtransmembrane domains of voltage-gated K⁺ channels. Kir subunits alsoassociate as tetramers. The Kir family includes ROMK1, mutations inwhich lead to Bartter syndrome, a renal tubular disorder. Kir channelsare also involved in regulation of cardiac pacemaker activity, seizuresand epilepsy, and insulin regulation (Doupnik, C. A. et al. (1995) Curr.Opin. Neurobiol. 5:268-277; Curran, supra).

[0028] The recently recognized TWIK K⁺ channel family includes themammalian TWIK-1, TREK-1 and TASK proteins. Members of this familypossess an overall structure with four transmembrane domains and two Pdomains. These proteins are probably involved in controlling the restingpotential in a large set of cell types (Duprat, F. et al. (1997) EMBO J16:5464-5471).

[0029] The voltage-gated Ca²⁺ channels have been classified into severalsubtypes based upon their electrophysiological and pharmacologicalcharacteristics. L-type Ca²⁺ channels are predominantly expressed inheart and skeletal muscle where they play an essential role inexcitation-contraction coupling. T-type channels are important forcardiac pacemaker activity, while N-type and P/Q-type channels areinvolved in the control of neurotransmitter release in the central andperipheral nervous system. The L-type and N-type voltage-gated Ca²⁺channels have been purified and, though their functions differdramatically, they have similar subunit compositions. The channels arecomposed of three subunits. The α₁ subunit forms the membrane pore andvoltage sensor, while the α₂δ and β subunits modulate thevoltage-dependence, gating properties, and the current amplitude of thechannel. These subunits are encoded by at least six α₁, one α₂δ and fourβ genes. A fourth subunit, γ, has been identified in skeletal muscle(Walker, D. et al. (1998) J. Biol. Chem. 273:2361-2367; McCleskey, E. W.(1994) Curr. Opin. Neurobiol. 4:304-312).

[0030] The transient receptor family (Trp) of calcium ion channels arethought to mediate capacitative calcium entry (CCE). CCE is the Ca²⁺influx into cells to resupply Ca²⁺ stores depleted by the action ofinositol triphosphate (IP3) and other agents in response to numeroushormones and growth factors. Trp and Trp-like were first cloned fromDrosophila and have similarity to voltage gated Ca2+ channels in the S3through S6 regions. This suggests that Trp and/or related proteins mayform mammalian CCC entry channels (Zhu, X. et al. (1996) Cell85:661-671; Boulay, G. et al. (1997) J. Biol. Chem. 272:29672-29680).Melastatin is a gene isolated in both the mouse and human, and whoseexpression in melanoma cells is inversely correlated with melanomaaggressiveness in vivo. The human cDNA transcript corresponds to a1533-amino acid protein having homology to members of the Trp family. Ithas been proposed that the combined use of malastatin mRNA expressionstatus and tumor thickness might allow for the determination ofsubgroups of patients at both low and high risk for developingmetastatic disease (Duncan, L. M. et al (2001) J. Clin. Oncol.19:568-576).

[0031] Chloride channels are necessary in endocrine secretion and inregulation of cytosolic and organelle pH. In secretory epithelial cells,Cl⁻ enters the cell across a basolateral membrane through an Na⁺, K⁺/Cl⁻cotransporter, accumulating in the cell above its electrochemicalequilibrium concentration. Secretion of Cl⁻ from the apical surface, inresponse to hormonal stimulation, leads to flow of Na⁺ and water intothe secretory lumen. The cystic fibrosis transmembrane conductanceregulator (CFTR) is a chloride channel encoded by the gene for cysticfibrosis, a common fatal genetic disorder in humans. CFTR is a member ofthe ABC transporter family, and is composed of two domains eachconsisting of six transmembrane domains followed by a nucleotide-bindingsite. Loss of CFTR function decreases transepithelial water secretionand, as a result, the layers of mucus that coat the respiratory tree,pancreatic ducts, and intestine are dehydrated and difficult to clear.The resulting blockage of these sites leads to pancreatic insufficiency,“meconium ileus”, and devastating “chronic obstructive pulmonarydisease” (Al-Awqati, Q. et al. (1992) J. Exp. Biol. 172:245-266).

[0032] The voltage-gated chloride channels (CLC) are characterized by10-12 transmembrane domains, as well as two small globular domains knownas CBS domains. The CLC subunits probably function as homotetramers. CLCproteins are involved in regulation of cell volume, membrane potentialstabilization, signal transduction, and transepithelial transport.Mutations in CLC-1, expressed predominantly in skeletal muscle, areresponsible for autosomal recessive generalized myotonia and autosomaldominant myotonia congenita, while mutations in the kidney channel CLC-5lead to kidney stones (Jentsch, T. J. (1996) Curr. Opin. Neurobiol.6:303-310).

[0033] Ligand-gated channels open their pores when an extracellular orintracellular mediator binds to the channel. Neurotransmitter-gatedchannels are channels that open when a neurotransmitter binds to theirextracellular domain. These channels exist in the postsynaptic membraneof nerve or muscle cells. There are two types of neurotransmitter-gatedchannels. Sodium channels open in response to excitatoryneurotransmitters, such as acetylcholine, glutamate, and serotonin. Thisopening causes an influx of Na⁺ and produces the initial localizeddepolarization that activates the voltage-gated channels and starts theaction potential. Chloride channels open in response to inhibitoryneurotransmitters, such as γ-aminobutyric acid (GABA) and glycine,leading to hyperpolarization of the membrane and the subsequentgeneration of an action potential. Neurotransmitter-gated ion channelshave four transmembrane domains and probably function as pentamers(Jentsch, supra). Amino acids in the second transmembrane domain appearto be important in determining channel permeation and selectivity(Sather, W. A. et al. (1994) Curr. Opin. Neurobiol. 4:313-323).

[0034] Ligand-gated channels can be regulated by intracellular secondmessengers. For example, calcium-activated K⁺ channels are gated byinternal calcium ions. In nerve cells, an influx of calcium duringdepolarization opens K⁺ channels to modulate the magnitude of the actionpotential (Ishi et al., supra). The large conductance (BK) channel hasbeen purified from brain and its subunit composition determined. The αsubunit of the BK channel has seven rather than six transmembranedomains in contrast to voltage-gated K⁺ channels. The extratransmembrane domain is located at the subunit N-terminus. A28-amino-acid stretch in the C-terminal region of the subunit (the“calcium bowl” region) contains many negatively charged residues and isthought to be the region responsible for calcium binding. The β subunitconsists of two transmembrane domains connected by a glycosylatedextracellular loop, with intracellular N- and C-termini (Kaczorowski,supra; Vergara, C. et al. (1998) Curr. Opin. Neurobiol. 8:321-329).

[0035] Cyclic nucleotide-gated (CNG) channels are gated by cytosoliccyclic nucleotides. The best examples of these are the cAMP-gated Na⁺channels involved in olfaction and the cGMP-gated cation channelsinvolved in vision. Both systems involve ligand-mediated activation of aG-protein coupled receptor which then alters the level of cyclicnucleotide within the cell. CNG channels also represent a major pathwayfor Ca²⁺ entry into neurons, and play roles in neuronal development andplasticity. CNG channels are tetramers containing at least two types ofsubunits, an a subunit which can form functional homomeric channels, anda β subunit, which modulates the channel properties. All CNG subunitshave six transmembrane domains and a pore forming region between thefifth and sixth transmembrane domains, similar to voltage-gated K⁺channels. A large C-terminal domain contains a cyclic nucleotide bindingdomain, while the N-terminal domain confers variation among channelsubtypes (Zufall, F. et al. (1997) Curr. Opin. Neurobiol. 7:404-412).

[0036] The activity of other types of ion channel proteins may also bemodulated by a variety of intracellular signalling proteins. Manychannels have sites for phosphorylation by one or more protein kinasesincluding protein kinase A, protein kinase C, tyrosine kinase, andcasein kinase II, all of which regulate ion channel activity in cells.Kir channels are activated by the binding of the Gβγ subunits ofheterotrimeric G-proteins (Reimann, F. and F. M. Ashcroft (1999) Curr.Opin. Cell. Biol. 11:503-508). Other proteins are involved in thelocalization of ion channels to specific sites in the cell membrane.Such proteins include the PDZ domain proteins known as MAGUKs(membrane-associated guanylate kinases) which regulate the clustering ofion channels at neuronal synapses (Craven, S. E. and D. S. Bredt (1998)Cell 93:495-498).

[0037] Disease Correlation

[0038] The etiology of numerous human diseases and disorders can beattributed to defects in the transport of molecules across membranes.Defects in the trafficking of membrane-bound transporters and ionchannels are associated with several disorders, e.g., cystic fibrosis,glucose-galactose malabsorption syndrome, hypercholesterolemia, vonGierke disease, and certain forms of diabetes mellitus. Single-genedefect diseases resulting in an inability to transport small moleculesacross membranes include, e.g., cystinuria, iminoglycinuria, Hartupdisease, and Fanconi disease (van't Hoff, W. G. (1996) Exp. Nephrol.4:253-262; Talente, G. M. et al. (1994) Ann. Intern. Med. 120:218-226;and Chillon, M. et al. (1995) New Engl. J. Med. 332:1475-1480).

[0039] Human diseases caused by mutations in ion channel genes includedisorders of skeletal muscle, cardiac muscle, and the central nervoussystem. Mutations in the pore-forming subunits of sodium and chloridechannels cause myotonia, a muscle disorder in which relaxation aftervoluntary contraction is delayed. Sodium channel myotonias have beentreated with channel blockers. Mutations in muscle sodium and calciumchannels cause forms of periodic paralysis, while mutations in thesarcoplasmic calcium release channel, T-tubule calcium channel, andmuscle sodium channel cause malignant hyperthermia. Cardiac arrythmiadisorders such as the long QT syndromes and idiopathic ventricularfibrillation are caused by mutations in potassium and sodium channels(Cooper, E. C. and L Y. January (1998) Proc. Natl. Acad. Sci. USA96:4759-4766). All four known human idiopathic epilepsy genes code forion channel proteins (Berkovic, S. F. and I. E. Scheffer (1999) Curr.Opin. Neurology 12:177-182). Other neurological disorders such asataxias, hemiplegic migraine and hereditary deafness can also resultfrom mutations in ion channel genes (Jen, J. (1999) Curr. Opin.Neurobiol. 9:274-280; Cooper, supra).

[0040] Several genetic diseases are attributed to defects in ABCtransporters, such as the following diseases and their correspondingproteins: cystic fibrosis (CFTR, an ion channel), adrenoleukodystrophy(adrenoleukodystrophy protein, ALDP), Zellweger syndrome (peroxisomalmembrane protein-70, PMP70), congenital hyperbilruginemia (MOAT),Stargart's disease, which causes defective vision in children (RIM/ABCR)and hyperinsulinemic hypoglycemia (sulfonylurea receptor, SUR) (Holland,B. and Blight, M. A. (1999) J. Mol. Biol. 293:381-399). Overexpressionof the multidrug resistance (MDR) protein in human cancer cells makesthe cells resistant to a variety of cytotoxic drugs used in chemotherapy(Taghght, D. and Michaelis, S. (1998) Meth. Enzymol. 292:131-163).

[0041] Two monomeric ABC transporters have been identified in the humanperoxisome membrane: the adrenoleukodystrophy protein (ALDP) and the70-kDa peroxisomal membrane protein (PMP70). Mutations in theadrenoleukodystrophy gene cause X-linked adrenoleukodystrophy, an inbornerror of peroxisomal β-oxidation of very long chain fatty acids.Mutations in the PMP70 genes have been found in patients with Zellwegersyndrome, an inborn error of peroxisome biogenesis. The sulfonylureareceptor, an ABC transporter, regulates the function of pancreaticATP-sensitive K⁺ channels, and sulphonylureas are widely used to treatnon-insulin dependent diabetes mellitus (Demolombe, S. and Escande, D.(1996) Trends Pharmacol. Sci. 17:273-275). Multidrug-resistance (MDR)results from overproduction of another member of the ABC transporterfamily, P-glycoprotein. MDR is primarily caused by increased drugextrusion from the resistant cells by P-glycoprotein. TheP-glycoproteins have 2 homologous halves, each with 6 hydrophobicsegments adjacent to a consensus sequence for nucleotide binding. Thehydrophobic segments may form a membrane channel, whereas the nucleotidebinding site may be involved in providing energy for drug transport(Saurin, W. et al. (1994) Mol. Microbiol. 12:993-1004; Shani, N., et al.(1996) J. Biol. Chem. 271:8725-8730; and Koster, W., and Bohm, B. (1992)Mol. & Gen. Genet. 232:399-407).

[0042] Ion channels have been the target for many drug therapies.Neurotransmitter-gated channels have been targeted in therapies fortreatment of insomnia, anxiety, depression, and schizophrenia.Voltage-gated channels have been targeted in therapies for arrhythmia,ischemic stroke, head trauma, and neurodegenerative disease (Taylor, C.P. and L. S. Narasimhan (1997) Adv. Pharmacol. 39:47-98). Variousclasses of ion channels also play an important role in the perception ofpain, and thus are potential targets for new analgesics. These includethe vanilloid-gated ion channels, which are activated by the vanilloidcapsaicin, as well as by noxious heat. Local anesthetics such aslidocaine and mexiletine which blockade voltage-gated Na⁺ channels havebeen useful in the treatment of neuropathic pain (Eglen, supra).

[0043] Ion channels in the immune system have recently been suggested astargets for immunomodulation. T-cell activation depends upon calciumsignaling, and a diverse set of T-cell specific ion channels has beencharacterized that affect this signaling process. Channel blockingagents can inhibit secretion of lymphokines, cell proliferation, andkilling of target cells. A peptide antagonist of the T-cell potassiumchannel Kv1.3 was found to suppress delayed-type hypersensitivity andallogenic responses in pigs, validating the idea of channel blockers assafe and efficacious immunosuppressants (Cahalan, M. D. and K. G. Chandy(1997) Curr. Opin. Biotechnol. 8:749-756).

[0044] The discovery of new transporters and ion channels and thepolynucleotides encoding them satisfies a need in the art by providingnew compositions which are useful in the diagnosis, prevention, andtreatment of transport, neurological, muscle, immunological, and cellproliferative disorders, and in the assessment of the effects ofexogenous compounds on the expression of nucleic acid and amino acidsequences of transporters and ion channels.

SUMMARY OF THE INVENTION

[0045] The invention features purified polypeptides, transporters andion channels, referred to collectively as “TRICH” and individually as“TRICH-1,” “TRICH-2,” “TRICH-3,” “TRICH-4,” “TRICH-5,” “TRICH-6,”“TRICH-7,” “TRICH-8,” “TRICH-9,” “TRICH-10,” “TRICH-11,” “TRICH-12,”“TRICH-13,” “TRICH-14,” “TRICH-15,” “TRICH-16,” “TRICH-17,” “TRICH-18,”“TRICH-19,” “TRICH-20,” “TRICH-21,” “TRICH-22,” “TRICH-23,” “TRICH-24,”“TRICH-25,” “TRICH-26,” and “TRICH-27.” In one aspect, the inventionprovides an isolated polypeptide selected from the group consisting ofa) a polypeptide comprising an amino acid sequence selected from thegroup consisting of SEQ ID NO: 1-27, b) a naturally occurringpolypeptide comprising an amino acid sequence at least 90% identical toan amino acid sequence selected from the group consisting of SEQ ID NO:1-27, c) a biologically active fragment of a polypeptide having an aminoacid sequence selected from the group consisting of SEQ ID NO: 1-27, andd) an immunogenic fragment of a polypeptide having an amino acidsequence selected from the group consisting of SEQ ID NO: 1-27. In onealternative, the invention provides an isolated polypeptide comprisingthe amino acid sequence of SEQ ID NO: 1-27.

[0046] The invention further provides an isolated polynucleotideencoding a polypeptide selected from the group consisting of a) apolypeptide comprising an amino acid sequence selected from the groupconsisting of SEQ ID NO: 1-27, b) a naturally occurring polypeptidecomprising an amino acid sequence at least 90% identical to an aminoacid sequence selected from the group consisting of SEQ ID NO: 1-27, c)a biologically active fragment of a polypeptide having an amino acidsequence selected from the group consisting of SEQ ID NO: 1-27, and d)an immunogenic fragment of a polypeptide having an amino acid sequenceselected from the group consisting of SEQ ID NO: 1-27. In onealternative, the polynucleotide encodes a polypeptide selected from thegroup consisting of SEQ ID NO: 1-27. In another alternative, thepolynucleotide is selected from the group consisting of SEQ ID NO:28-54.

[0047] Additionally, the invention provides a recombinant polynucleotidecomprising a promoter sequence operably linked to a polynucleotideencoding a polypeptide selected from the group consisting of a) apolypeptide comprising an amino acid sequence selected from the groupconsisting of SEQ ID NO: 1-27, b) a naturally occurring polypeptidecomprising an amino acid sequence at least 90% identical to an aminoacid sequence selected from the group consisting of SEQ ID NO: 1-27, c)a biologically active fragment of a polypeptide having an amino acidsequence selected from the group consisting of SEQ ID NO: 1-27, and d)an immunogenic fragment of a polypeptide having an amino acid sequenceselected from the group consisting of SEQ ID NO: 1-27. In onealternative, the invention provides a cell transformed with therecombinant polynucleotide. In another alternative, the inventionprovides a transgenic organism comprising the recombinantpolynucleotide.

[0048] The invention also provides a method for producing a polypeptideselected from the group consisting of a) a polypeptide comprising anamino acid sequence selected from the group consisting of SEQ ID NO:1-27, b) a naturally occurring polypeptide comprising an amino acidsequence at least 90% identical to an amino acid sequence selected fromthe group consisting of SEQ ID NO: 1-27, c) a biologically activefragment of a polypeptide having an amino acid sequence selected fromthe group consisting of SEQ ID NO: 1-27, and d) an immunogenic fragmentof a polypeptide having an amino acid sequence selected from the groupconsisting of SEQ ID NO: 1-27. The method comprises a) culturing a cellunder conditions suitable for expression of the polypeptide, whereinsaid cell is transformed with a recombinant polynucleotide comprising apromoter sequence operably linked to a polynucleotide encoding thepolypeptide, and b) recovering the polypeptide so expressed.

[0049] Additionally, the invention provides an isolated antibody whichspecifically binds to a polypeptide selected from the group consistingof a) a polypeptide comprising an amino acid sequence selected from thegroup consisting of SEQ ID NO: 1-27, b) a naturally occurringpolypeptide comprising an amino acid sequence at least 90% identical toan amino acid sequence selected from the group consisting of SEQ ID NO:1-27, c) a biologically active fragment of a polypeptide having an aminoacid sequence selected from the group consisting of SEQ ID NO: 1-27, andd) an immunogenic fragment of a polypeptide having an amino acidsequence selected from the group consisting of SEQ ID NO: 1-27.

[0050] The invention further provides an isolated polynucleotideselected from the group consisting of a) a polynucleotide comprising apolynucleotide sequence selected from the group consisting of SEQ ID NO:28-54, b) a naturally occurring polynucleotide comprising apolynucleotide sequence at least 90% identical to a polynucleotidesequence selected from the group consisting of SEQ ID NO: 28-54, c) apolynucleotide complementary to the polynucleotide of a), d) apolynucleotide complementary to the polynucleotide of b), and e) an RNAequivalent of a)-d). In one alternative, the polynucleotide comprises atleast 60 contiguous nucleotides.

[0051] Additionally, the invention provides a method for detecting atarget polynucleotide in a sample, said target polynucleotide having asequence of a polynucleotide selected from the group consisting of a) apolynucleotide comprising a polynucleotide sequence selected from thegroup consisting of SEQ ID NO: 28-54, b) a naturally occurringpolynucleotide comprising a polynucleotide sequence at least 90%identical to a polynucleotide sequence selected from the groupconsisting of SEQ ID NO: 28-54, c) a polynucleotide complementary to thepolynucleotide of a), d) a polynucleotide complementary to thepolynucleotide of b), and e) an RNA equivalent of a)-d). The methodcomprises a) hybridizing the sample with a probe comprising at least 20contiguous nucleotides comprising a sequence complementary to saidtarget polynucleotide in the sample, and which probe specificallyhybridizes to said target polynucleotide, under conditions whereby ahybridization complex is formed between said probe and said targetpolynucleotide or fragments thereof, and b) detecting the presence orabsence of said hybridization complex, and optionally, if present, theamount thereof. In one alternative, the probe comprises at least 60contiguous nucleotides.

[0052] The invention further provides a method for detecting a targetpolynucleotide in a sample, said target polynucleotide having a sequenceof a polynucleotide selected from the group consisting of a) a:polynucleotide comprising a polynucleotide sequence selected from thegroup consisting of SEQ ID NO: 28-54, b) a naturally occurringpolynucleotide comprising a polynucleotide sequence at least 90%identical to a polynucleotide sequence selected from the groupconsisting of SEQ ID NO: 28-54, c) a polynucleotide complementary to thepolynucleotide of a), d) a polynucleotide complementary to thepolynucleotide of b), and e) an RNA equivalent of a)-d). The methodcomprises a) amplifying said target polynucleotide or fragment thereofusing polymerase chain reaction amplification, and b) detecting thepresence or absence of said amplified target polynucleotide or fragmentthereof, and, optionally, if present, the amount thereof.

[0053] The invention further provides a composition comprising aneffective amount of a polypeptide selected from the group consisting ofa) a polypeptide comprising an amino acid sequence selected from thegroup consisting of SEQ ID NO: 1-27, b) a naturally occurringpolypeptide comprising an amino acid sequence at least 90% identical toan amino acid sequence selected from the group consisting of SEQ ID NO:1-27, c) a biologically active fragment of a polypeptide having an aminoacid sequence selected from the group consisting of SEQ ID NO: 1-27, andd) an immunogenic fragment of a polypeptide having an amino acidsequence selected from the group consisting of SEQ ID NO: 1-27, and apharmaceutically acceptable excipient. In one embodiment, thecomposition comprises an amino acid sequence selected from the groupconsisting of SEQ ID NO: 1-27. The invention additionally provides amethod of treating a disease or condition associated with decreasedexpression of functional TRICH, comprising administering to a patient inneed of such treatment the composition.

[0054] The invention also provides a method for screening a compound foreffectiveness as an agonist of a polypeptide selected from the groupconsisting of a) a polypeptide comprising an amino acid sequenceselected from the group consisting of SEQ ID NO: 1-27, b) a naturallyoccurring polypeptide comprising an amino acid sequence at least 90%identical to an amino acid sequence selected from the group consistingof SEQ ID NO: 1-27, c) a biologically active fragment of a polypeptidehaving an amino acid sequence selected from the group consisting of SEQID NO: 1-27, and d) an immunogenic fragment of a polypeptide having anamino acid sequence selected from the group consisting of SEQ ID NO:1-27. The method comprises a) exposing a sample comprising thepolypeptide to a compound, and b) detecting agonist activity in thesample. In one alternative, the invention provides a compositioncomprising an agonist compound identified by the method and apharmaceutically acceptable excipient. In another alternative, theinvention provides a method of treating a disease or conditionassociated with decreased expression of functional TRICH, comprisingadministering to a patient in need of such treatment the composition

[0055] Additionally, the invention provides a method for screening acompound for effectiveness as an antagonist of a polypeptide selectedfrom the group consisting of a) a polypeptide comprising an amino acidsequence selected from the group consisting of SEQ ID NO: 1-27, b) anaturally occurring polypeptide comprising an amino acid sequence atleast 90% identical to an amino acid sequence selected from the groupconsisting of SEQ ID NO: 1-27, c) a biologically active fragment of apolypeptide having an amino acid sequence selected from the groupconsisting of SEQ ID NO: 1-27, and d) an immunogenic fragment of apolypeptide having an amino acid sequence selected from the groupconsisting of SEQ ID NO: 1-27. The method comprises a) exposing a samplecomprising the polypeptide to a compound, and b) detecting antagonistactivity in the sample. In one alternative, the invention provides acomposition comprising an antagonist compound identified by the methodand a pharmaceutically acceptable excipient. In another alternative, theinvention provides a method of treating a disease or conditionassociated with overexpression of functional TRICH, comprisingadministering to a patient in need of such treatment the composition.

[0056] The invention further provides a method of screening for acompound that specifically binds to a polypeptide selected from thegroup consisting of a) a polypeptide comprising an amino acid sequenceselected from the group consisting of SEQ ID NO: 1-27, b) a naturallyoccurring polypeptide comprising an amino acid sequence at least 90%identical to an amino acid sequence selected from the group consistingof SEQ ID NO: 1-27, c) a biologically active fragment of a polypeptidehaving an amino acid sequence selected from the group consisting of SEQID NO: 1-27, and d) an immunogenic fragment of a polypeptide having anamino acid sequence selected from the group consisting of SEQ ID NO:1-27. The method comprises a) combining the polypeptide with at leastone test compound under suitable conditions, and b) detecting binding ofthe polypeptide to the test compound, thereby identifying a compoundthat specifically binds to the polypeptide.

[0057] The invention further provides a method of screening for acompound that modulates the activity of a polypeptide selected from thegroup consisting of a) a polypeptide comprising an amino acid sequenceselected from the group consisting of SEQ ID NO: 1-27, b) a naturallyoccurring polypeptide comprising an amino acid sequence at least 90%identical to an amino acid sequence selected from the group consistingof SEQ ID NO: 1-27, c) a biologically active fragment of a polypeptidehaving an amino acid sequence selected from the group consisting of SEQID NO: 1-27, and d) an immunogenic fragment of a polypeptide having anamino acid sequence selected from the group consisting of SEQ ID NO:1-27. The method comprises a) combining the polypeptide with at leastone test compound under conditions permissive for the activity of thepolypeptide, b) assessing the activity of the polypeptide in thepresence of the test compound, and c) comparing the activity of thepolypeptide in the presence of the test compound with the activity ofthe polypeptide in the absence of the test compound, wherein a change inthe activity of the polypeptide in the presence of the test compound isindicative of a compound that modulates the activity of the polypeptide.

[0058] The invention further provides a method for screening a compoundfor effectiveness in altering expression of a target polynucleotide,wherein said target polynucleotide comprises a sequence selected fromthe group consisting of SEQ ID NO: 28-54, the method comprising a)exposing a sample comprising the target polynucleotide to a compound,and b) detecting altered expression of the target polynucleotide.

[0059] The invention further provides a method for assessing toxicity ofa test compound, said method comprising a) treating a biological samplecontaining nucleic acids with the test compound; b) hybridizing thenucleic acids of the treated biological sample with a probe comprisingat least 20 contiguous nucleotides of a polynucleotide selected from thegroup consisting of i) a polynucleotide comprising a polynucleotidesequence selected from the group consisting of SEQ ID NO: 28-54, ii) anaturally occurring polynucleotide comprising a polynucleotide sequenceat least 90% identical to a polynucleotide sequence selected from thegroup consisting of SEQ ID NO: 28-54, iii) a polynucleotide having asequence complementary to i), iv) a polynucleotide complementary to thepolynucleotide of ii), and v) an RNA equivalent of i)-iv). Hybridizationoccurs under conditions whereby a specific hybridization complex isformed between said probe and a target polynucleotide in the biologicalsample, said target polynucleotide selected from the group consisting ofi) a polynucleotide comprising a polynucleotide sequence selected fromthe group consisting of SEQ ID NO: 28-54, ii) a naturally occurringpolynucleotide comprising a polynucleotide sequence at least 90%identical to a polynucleotide sequence selected from the groupconsisting of SEQ ID NO: 28-54, iii) a polynucleotide complementary tothe polynucleotide of i), iv) a polynucleotide complementary to thepolynucleotide of ii), and v) an RNA equivalent of i)-iv).Alternatively, the target polynucleotide comprises a fragment of apolynucleotide sequence selected from the group consisting of i)-v)above; c) quantifying the amount of hybridization complex; and d)comparing the amount of hybridization complex in the treated biologicalsample with the amount of hybridization complex in an untreatedbiological sample, wherein a difference in the amount of hybridizationcomplex in the treated biological sample is indicative of toxicity ofthe test compound.

BRIEF DESCRIPTION OF THE TABLES

[0060] Table 1 summarizes the nomenclature for the full lengthpolynucleotide and polypeptide sequences of the present invention.

[0061] Table 2 shows the GenBank identification number and annotation ofthe nearest GenBank homolog for polypeptides of the invention. Theprobability score for the match between each polypeptide and its GenBankhomolog is also shown.

[0062] Table 3 shows structural features of polypeptide sequences of theinvention, including predicted motifs and domains, along with themethods, algorithms, and searchable databases used for analysis of thepolypeptides.

[0063] Table 4 lists the cDNA and/or genomic DNA fragments which wereused to assemble polynucleotide sequences of the invention, along withselected fragments of the polynucleotide sequences.

[0064] Table 5 shows the representative cDNA library for polynucleotidesof the invention.

[0065] Table 6 provides an appendix which describes the tissues andvectors used for construction of the cDNA libraries shown in Table 5.

[0066] Table 7 shows the tools, programs, and algorithms used to analyzethe polynucleotides and polypeptides of the invention, along withapplicable descriptions, references, and threshold parameters.

DESCRIPTION OF THE INVENTION

[0067] Before the present proteins, nucleotide sequences, and methodsare described, it is understood that this invention is not limited tothe particular machines, materials and methods described, as these mayvary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments only, and is notintended to limit the scope of the present invention which will belimited only by the appended claims.

[0068] It must be noted that as used herein and in the appended claims,the singular forms “a,” “an,” and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, a referenceto “a host cell” includes a plurality of such host cells, and areference to “an antibody” is a reference to one or more antibodies andequivalents thereof known to those skilled in the art, and so forth.

[0069] Unless defined otherwise, all technical and scientific terms usedherein have the same meanings as commonly understood by one of ordinaryskill in the art to which this invention belongs. Although any machines,materials, and methods similar or equivalent to those described hereincan be used to practice or test the present invention, the preferredmachines, materials and methods are now described. All publicationsmentioned herein are cited for the purpose of describing and disclosingthe cell lines, protocols, reagents and vectors which are reported inthe publications and which might be used in connection with theinvention. Nothing herein is to be construed as an admission that theinvention is not entitled to antedate such disclosure by virtue of priorinvention.

[0070] Definitions

[0071] “TRICH” refers to the amino acid sequences of substantiallypurified TRICH obtained from any species, particularly a mammalianspecies, including bovine, ovine, porcine, murine, equine, and human,and from any source, whether natural, synthetic, semi-synthetic, orrecombinant

[0072] The term “agonist” refers to a molecule which intensifies ormimics the biological activity of TRICH. Agonists may include proteins,nucleic acids, carbohydrates, small molecules, or any other compound orcomposition which modulates the activity of TRICH either by directlyinteracting with TRICH or by acting on components of the biologicalpathway in which TRICH participates.

[0073] An “allelic variant” is an alternative form of the gene encodingTRICH. Allelic variants may result from at least one mutation in thenucleic acid sequence and may result in altered mRNAs or in polypeptideswhose structure or function may or may not be altered. A gene may havenone, one, or many allelic variants of its naturally occurring form.Common mutational changes which give rise to allelic variants aregenerally ascribed to natural deletions, additions, or substitutions ofnucleotides. Each of these types of changes may occur alone, or incombination with the others, one or more times in a given sequence.

[0074] “Altered” nucleic acid sequences encoding TRICH include thosesequences with deletions, insertions, or substitutions of differentnucleotides, resulting in a polypeptide the same as TRICH or apolypeptide with at least one functional characteristic of TRICH.Included within this definition are polymorphisms which may or may notbe readily detectable using a particular oligonucleotide probe of thepolynucleotide encoding TRICH, and improper or unexpected hybridizationto allelic variants, with a locus other than the normal chromosomallocus for the polynucleotide sequence encoding TRICH. The encodedprotein may also be “altered,” and may contain deletions, insertions, orsubstitutions of amino acid residues which produce a silent change andresult in a functionally equivalent TRICH. Deliberate amino acidsubstitutions may be made on the basis of similarity in polarity,charge, solubility, hydrophobicity, hydrophilicity, and/or theamphipathic nature of the residues, as long as the biological orimmunological activity of TRICH is retained. For example, negativelycharged amino acids may include aspartic acid and glutamic acid, andpositively charged amino acids may include lysine and arginine. Aminoacids with uncharged polar side chains having similar hydrophilicityvalues may include: asparagine and glutamine; and serine and threonine.Amino acids with uncharged side chains having similar hydrophilicityvalues may include: leucine, isoleucine, and valine; glycine andalanine; and phenylalanine and tyrosine.

[0075] The terms “amino acid” and “amino acid sequence” refer to anoligopeptide, peptide, polypeptide, or protein sequence, or a fragmentof any of these, and to naturally occurring or synthetic molecules.Where “amino acid sequence” is recited to refer to a sequence of anaturally occurring protein molecule, “amino acid sequence” and liketerms are not meant to limit the amino acid sequence to the completenative amino acid sequence associated with the recited protein molecule.

[0076] “Amplification” relates to the production of additional copies ofa nucleic acid sequence. Amplification is generally carried out usingpolymerase chain reaction (PCR) technologies well known in the art.

[0077] The term “antagonist” refers to a molecule which inhibits orattenuates the biological activity of TRICH. Antagonists may includeproteins such as antibodies, nucleic acids, carbohydrates, smallmolecules, or any other compound or composition which modulates theactivity of TRICH either by directly interacting with TRICH or by actingon components of the biological pathway in which TRICH participates.

[0078] The term “antibody” refers to intact immunoglobulin molecules aswell as to fragments thereof, such as Fab, F(ab′)₂, and Fv fragments,which are capable of binding an epitopic determinant. Antibodies thatbind TRICH polypeptides can be prepared using intact polypeptides orusing fragments containing small peptides of interest as the immunizingantigen. The polypeptide or oligopeptide used to immunize an animal(e.g., a mouse, a rat, or a rabbit) can be derived from the translationof RNA, or synthesized chemically, and can be conjugated to a carrierprotein if desired. Commonly used carriers that are chemically coupledto peptides include bovine serum albumin, thyroglobulin, and keyholelimpet hemocyanin (KLH). The coupled peptide is then used to immunizethe animal.

[0079] The term “antigenic determinant” refers to that region of amolecule (i.e., an epitope) that makes contact with a particularantibody. When a protein or a fragment of a protein is used to immunizea host animal, numerous regions of the protein may induce the productionof antibodies which bind specifically to antigenic determinants(particular regions or three-dimensional structures on the protein). Anantigenic determinant may compete with the intact antigen (i.e., theimmunogen used to elicit the immune response) for binding to anantibody.

[0080] The term “antisense” refers to any composition capable ofbase-pairing with the “sense” (coding) strand of a specific nucleic acidsequence. Antisense compositions may include DNA; RNA; peptide nucleicacid (PNA); oligonucleotides having modified backbone linkages such asphosphorothioates, methylphosphonates, or benzylphosphonates;oligonucleotides having modified sugar groups such as 2′-methoxyethylsugars or 2′-methoxyethoxy sugars; or oligonucleotides having modifiedbases such as 5-methyl cytosine, 2′-deoxyuracil, or7-deaza-2′-deoxyguanosine. Antisense molecules may be produced by anymethod including chemical synthesis or transcription. Once introducedinto a cell, the complementary antisense molecule base-pairs with anaturally occurring nucleic acid sequence produced by the cell to formduplexes which block either transcription or translation. Thedesignation “negative” or “minus” can refer to the antisense strand, andthe designation “positive” or “plus” can refer to the sense strand of areference DNA molecule.

[0081] The term “biologically active” refers to a protein havingstructural, regulatory, or biochemical functions of a naturallyoccurring molecule. Likewise, “immunologically active” or “immunogenic”refers to the capability of the natural, recombinant, or syntheticTRICH, or of any oligopeptide thereof, to induce a specific immuneresponse in appropriate animals or cells and to bind with specificantibodies.

[0082] “Complementary” describes the relationship between twosingle-stranded nucleic acid sequences that anneal by base-pairing. Forexample, 5′-AGT-3′ pairs with its complement, 3′-TCA-5′.

[0083] A “composition comprising a given polynucleotide sequence” and a“composition comprising a given amino acid sequence” refer broadly toany composition containing the given polynucleotide or amino acidsequence. The composition may comprise a dry formulation or an aqueoussolution. Compositions comprising polynucleotide sequences encodingTRICH or fragments of TRICH may be employed as hybridization probes. Theprobes may be stored in freeze-dried form and may be associated with astabilizing agent such as a carbohydrate. In hybridizations, the probemay be deployed in an aqueous solution containing salts (e.g., NaCl),detergents (e.g., sodium dodecyl sulfate; SDS), and other components(e.g., Denhardt's solution, dry milk, salmon sperm DNA, etc.).

[0084] “Consensus sequence” refers to a nucleic acid sequence which hasbeen subjected to repeated DNA sequence analysis to resolve uncalledbases, extended using the XL-PCR kit (Applied Biosystems, Foster CityCalif.) in the 5′ and/or the 3′ direction, and resequenced, or which hasbeen assembled from one or more overlapping cDNA, EST, or genomic DNAfragments using a computer program for fragment assembly, such as theGELVIEW fragment assembly system (GCG, Madison Wis.) or Phrap(University of Washington, Seattle Wash.). Some sequences have been bothextended and assembled to produce the consensus sequence.

[0085] “Conservative amino acid substitutions” are those substitutionsthat are predicted to least interfere with the properties of theoriginal protein, i.e., the structure and especially the function of theprotein is conserved and not significantly changed by suchsubstitutions. The table below shows amino acids which may besubstituted for an original amino acid in a protein and which areregarded as conservative amino acid substitutions. Original ResidueConservative Substitution Ala Gly, Ser Arg His, Lys Asn Asp, Gln, HisAsp Asn, Glu Cys Ala, Ser Gln Asn, Glu, His Glu Asp, Gln, His Gly AlaHis Asn, Arg, Gln, Glu Ile Leu, Val Leu Ile, Val Lys Arg, Gln, Glu MetLeu, Ile Phe His, Met, Leu, Trp, Tyr Ser Cys, Thr Thr Ser, Val Trp Phe,Tyr Tyr His, Phe, Trp Val Ile, Leu, Thr

[0086] Conservative amino acid substitutions generally maintain (a) thestructure of the polypeptide backbone in the area of the substitution,for example, as a beta sheet or alpha helical conformation, (b) thecharge or hydrophobicity of the molecule at the site of thesubstitution, and/or (c) the bulk of the side chain.

[0087] A “deletion” refers to a change in the amino acid or nucleotidesequence that results in the absence of one or more amino acid residuesor nucleotides.

[0088] The term “derivative” refers to a chemically modifiedpolynucleotide or polypeptide. Chemical modifications of apolynucleotide can include, for example, replacement of hydrogen by analkyl, acyl, hydroxyl, or amino group. A derivative polynucleotideencodes a polypeptide which retains at least one biological orimmunological function of the natural molecule. A derivative polypeptideis one modified by glycosylation, pegylation, or any similar processthat retains at least one biological or immunological function of thepolypeptide from which it was derived.

[0089] A “detectable label” refers to a reporter molecule or enzyme thatis capable of generating a measurable signal and is covalently ornoncovalently joined to a polynucleotide or polypeptide.

[0090] “Differential expression” refers to increased or upregulated; ordecreased, downregulated, or absent gene or protein expression,determined by comparing at least two different samples. Such comparisonsmay be carried out between, for example, a treated and an untreatedsample, or a diseased and a normal sample.

[0091] A “fragment” is a unique portion of TRICH or the polynucleotideencoding TRICH which is identical in sequence to but shorter in lengththan the parent sequence. A fragment may comprise up to the entirelength of the defined sequence, minus one nucleotide/amino acid residue.For example, a fragment may comprise from 5 to 1000 contiguousnucleotides or amino acid residues. A fragment used as a probe, primer,antigen, therapeutic molecule, or for other purposes, may be at least 5,10, 15, 16, 20, 25, 30, 40, 50, 60, 75, 100, 150, 250 or at least 500contiguous nucleotides or amino acid residues in length. Fragments maybe preferentially selected from certain regions of a molecule. Forexample, a polypeptide fragment may comprise a certain length ofcontiguous amino acids selected from the first 250 or 500 amino acids(or first 25% or 50%) of a polypeptide as shown in a certain definedsequence. Clearly these lengths are exemplary, and any length that issupported by the specification, including the Sequence Listing, tables,and figures, may be encompassed by the present embodiments.

[0092] A fragment of SEQ ID NO: 28-54 comprises a region of uniquepolynucleotide sequence that specifically identifies SEQ ID NO: 28-54,for example, as distinct from any other sequence in the genome fromwhich the fragment was obtained. A fragment of SEQ ID NO: 28-54 isuseful, for example, in hybridization and amplification technologies andin analogous methods that distinguish SEQ ID NO: 28-54 from relatedpolynucleotide sequences. The precise length of a fragment of SEQ ID NO:28-54 and the region of SEQ ID NO: 28-54 to which the fragmentcorresponds are routinely determinable by one of ordinary skill in theart based on the intended purpose for the fragment.

[0093] A fragment of SEQ ID NO: 1-27 is encoded by a fragment of SEQ IDNO: 28-54. A fragment of SEQ ID NO: 1-27 comprises a region of uniqueamino acid sequence that specifically identifies SEQ ID NO: 1-27. Forexample, a fragment of SEQ ID NO: 1-27 is useful as an immunogenicpeptide for the development of antibodies that specifically recognizeSEQ ID NO: 1-27. The precise length of a fragment of SEQ ID NO: 1-27 andthe region of SEQ ID NO: 1-27 to which the fragment corresponds areroutinely determinable by one of ordinary skill in the art based on theintended purpose for the fragment.

[0094] A “full length” polynucleotide sequence is one containing atleast a translation initiation codon (e.g., methionine) followed by anopen reading frame and a translation termination codon. A “fall length”polynucleotide sequence encodes a “full length” polypeptide sequence.

[0095] “Homology” refers to sequence similarity or, interchangeably,sequence identity, between two or more polynucleotide sequences or twoor more polypeptide sequences.

[0096] The terms “percent identity” and “% identity,” as applied topolynucleotide sequences, refer to the percentage of residue matchesbetween at least two polynucleotide sequences aligned using astandardized algorithm. Such an algorithm may insert, in a standardizedand reproducible way, gaps in the sequences being compared in order tooptimize alignment between two sequences, and therefore achieve a moremeaningful comparison of the two sequences.

[0097] Percent identity between polynucleotide sequences may bedetermined using the default parameters of the CLUSTAL V algorithm asincorporated into the MEGALIGN version 3.12e sequence alignment program.This program is part of the LASERGENE software package, a suite ofmolecular biological analysis programs (DNASTAR, Madison Wis.). CLUSTALV is described in Higgins, D. G. and P. M. Sharp (1989) CABIOS 5:151-153and in Higgins, D. G. et al. (1992) CABIOS 8:189-191. For pairwisealignments of polynucleotide sequences, the default parameters are setas follows: Ktuple=2, gap penalty=5, window=4, and “diagonals saved”=4.The “weighted” residue weight table is selected as the default. Percentidentity is reported by CLUSTAL V as the “percent similarity” betweenaligned polynucleotide sequences.

[0098] Alternatively, a suite of commonly used and freely availablesequence comparison algorithms is provided by the National Center forBiotechnology Information (NCBI) Basic Local Alignment Search Tool(BLAST) (Altschul, S. F. et al. (1990) J. Mol. Biol. 215:403-410), whichis available from several sources, including the NCBI, Bethesda, Md.,and on the Internet at http://www.ncbi.nlm.nih.gov/BLAST/. The BLASTsoftware suite includes various sequence analysis programs including“blastn,” that is used to align a known polynucleotide sequence withother polynucleotide sequences from a variety of databases. Alsoavailable is a tool called “BLAST 2 Sequences” that is used for directpairwise comparison of two nucleotide sequences. “BLAST 2 Sequences” canbe accessed and used interactively athttp://www.ncbi.nlm.nih.gov/gorf/b12.html. The “BLAST 2 Sequences” toolcan be used for both blastn and blastp (discussed below). BLAST programsare commonly used with gap and other parameters set to default settings.For example, to compare two nucleotide sequences, one may use blastnwith the “BLAST 2 Sequences” tool Version 2.0.12 (Apr. 21, 2000) set atdefault parameters. Such default parameters may be, for example:

[0099] Matrix: BLOSUM62

[0100] Reward for match: 1

[0101] Penalty for mismatch: −2

[0102] Open Gap: 5 and Extension Gap: 2 penalties

[0103] Gap×drop-off: 50

[0104] Expect: 10

[0105] Word Size: 11

[0106] Filter: on

[0107] Percent identity may be measured over the length of an entiredefined sequence, for example, as defined by a particular SEQ ID number,or may be measured over a shorter length, for example, over the lengthof a fragment taken from a larger, defined sequence, for instance, afragment of at least 20, at least 30, at least 40, at least 50, at least70, at least 100, or at least 200 contiguous nucleotides. Such lengthsare exemplary only, and it is understood that any fragment lengthsupported by the sequences shown herein, in the tables, figures, orSequence Listing, may be used to describe a length over which percentageidentity may be measured.

[0108] Nucleic acid sequences that do not show a high degree of identitymay nevertheless encode similar amino acid sequences due to thedegeneracy of the genetic code. It is understood that changes in anucleic acid sequence can be made using this degeneracy to producemultiple nucleic acid sequences that all encode substantially the sameprotein.

[0109] The phrases “percent identity” and “% identity,” as applied topolypeptide sequences, refer to the percentage of residue matchesbetween at least two polypeptide sequences aligned using a standardizedalgorithm. Methods of polypeptide sequence alignment are well-known.Some alignment methods take into account conservative amino acidsubstitutions. Such conservative substitutions, explained in more detailabove, generally preserve the charge and hydrophobicity at the site ofsubstitution, thus preserving the structure (and therefore function) ofthe polypeptide.

[0110] Percent identity between polypeptide sequences may be determinedusing the default parameters of the CLUSTAL V algorithm as incorporatedinto the MEGALIGN version 3.12e sequence alignment program (describedand referenced above). For pairwise alignments of polypeptide sequencesusing CLUSTAL V, the default parameters are set as follows: Ktuple=1,gap penalty=3, window=5, and “diagonals saved”=5. The PAM250 matrix isselected as the default residue weight table. As with polynucleotidealignments, the percent identity is reported by CLUSTAL V as the“percent similarity” between aligned polypeptide sequence pairs.

[0111] Alternatively the NCBI BLAST software suite may be used. Forexample, for a pairwise comparison of two polypeptide sequences, one mayuse the “BLAST 2 Sequences” tool Version 2.0.12 (Apr. 21, 2000) withblastp set at default parameters. Such default parameters may be, forexample;

[0112] Matrix: BLOSUM62

[0113] Open Gap: 11 and Extension Gap: 1 penalties

[0114] Gap×drop-off: 50

[0115] Expect: 10

[0116] Word Size: 3

[0117] Filter: on

[0118] Percent identity may be measured over the length of an entiredefined polypeptide sequence, for example, as defined by a particularSEQ ID number, or may be measured over a shorter length, for example,over the length of a fragment taken from a larger, defined polypeptidesequence, for instance, a fragment of at least 15, at least 20, at least30, at least 40, at least 50, at least 70 or at least 150 contiguousresidues. Such lengths are exemplary only, and it is understood that anyfragment length supported by the sequences shown herein, in the tables,figures or Sequence Listing, may be used to describe a length over whichpercentage identity may be measured.

[0119] “Human artificial chromosomes” (HACs) are linear microchromosomeswhich may contain DNA sequences of about 6 kb to 10 Mb in size and whichcontain all of the elements required for chromosome replication,segregation and maintenance.

[0120] The term “humanized antibody” refers to an antibody molecule inwhich the amino acid sequence in the non-antigen binding regions hasbeen altered so that the antibody more closely resembles a humanantibody, and still retains its original binding ability.

[0121] “Hybridization” refers to the process by which a polynucleotidestrand anneals with a complementary strand through base pairing underdefined hybridization conditions. Specific hybridization is anindication that two nucleic acid sequences share a high degree ofcomplementarity. Specific hybridization complexes form under permissiveannealing conditions and remain hybridized after the “washing” step(s).The washing step(s) is particularly important in determining thestringency of the hybridization process, with more stringent conditionsallowing less non-specific binding, i.e., binding between pairs ofnucleic acid strands that are not perfectly matched. Permissiveconditions for annealing of nucleic acid sequences are routinelydeterminable by one of ordinary skill in the art and may be consistentamong hybridization experiments, whereas wash conditions may be variedamong experiments to achieve the desired stringency, and thereforehybridization specificity. Permissive annealing conditions occur, forexample, at 68° C. in the presence of about 6×SSC, about 1% (w/v) SDS,and about 100 μg/ml sheared, denatured salmon sperm DNA.

[0122] Generally, stringency of hybridization is expressed, in part,with reference to the temperature under which the wash step is carriedout. Such wash temperatures are typically selected to be about 5° C. to20° C. lower than the thermal melting point (T_(m)) for the specificsequence at a defined ionic strength and pH. The T_(m) is thetemperature (under defined ionic strength and pH) at which 50% of thetarget sequence hybridizes to a perfectly matched probe. An equation forcalculating T_(m) and conditions for nucleic acid hybridization are wellknown and can be found in Sambrook, J. et al. (1989) Molecular Cloning:A Laboratory Manual, 2^(nd) ed., vol. 1-3, Cold Spring Harbor Press,Plainview N.Y.; specifically see volume 2, chapter 9.

[0123] High stringency conditions for hybridization betweenpolynucleotides of the present invention include wash conditions of 68°C. in the presence of about 0.2×SSC and about 0.1% SDS, for 1 hour.Alternatively, temperatures of about 65° C., 60° C., 55° C., or 42° C.may be used. SSC concentration may be varied from about 0.1 to 2×SSC,with SDS being present at about 0.1%. Typically, blocking reagents areused to block non-specific hybridization. Such blocking reagentsinclude, for instance, sheared and denatured salmon sperm DNA at about100-200 μg/ml. Organic solvent, such as formamide at a concentration ofabout 35-50% v/v, may also be used under particular circumstances, suchas for RNA:DNA hybridizations. Useful variations on these washconditions will be readily apparent to those of ordinary skill in theart. Hybridization, particularly under high stringency conditions, maybe suggestive of evolutionary similarity between the nucleotides. Suchsimilarity is strongly indicative of a similar role for the nucleotidesand their encoded polypeptides.

[0124] The term “hybridization complex” refers to a complex formedbetween two nucleic acid sequences by virtue of the formation ofhydrogen bonds between complementary bases. A hybridization complex maybe formed in solution (e.g., C₀t or R₀t analysis) or formed between onenucleic acid sequence present in solution and another nucleic acidsequence immobilized on a solid support (e.g., paper, membranes,filters, chips, pins or glass slides, or any other appropriate substrateto which cells or their nucleic acids have been fixed).

[0125] The words “insertion” and “addition” refer to changes in an aminoacid or nucleotide sequence resulting in the addition of one or moreamino acid residues or nucleotides, respectively.

[0126] “Immune response” can refer to conditions associated withinflammation, trauma, immune disorders, or infectious or geneticdisease, etc. These conditions can be characterized by expression ofvarious factors, e.g., cytokines, chemokines, and other signalingmolecules, which may affect cellular and systemic defense systems.

[0127] An “immunogenic fragment” is a polypeptide or oligopeptidefragment of TRICH which is capable of eliciting an immune response whenintroduced into a living organism, for example, a mammal. The term“immunogenic fragment” also includes any polypeptide or oligopeptidefragment of TRICH which is useful in any of the antibody productionmethods disclosed herein or known in the art.

[0128] The term “microarray” refers to an arrangement of a plurality ofpolynucleotides, polypeptides, or other chemical compounds on asubstrate.

[0129] The terms “element” and “array element” refer to apolynucleotide, polypeptide, or other chemical compound having a uniqueand defined position on a microarray.

[0130] The term “modulate” refers to a change in the activity of TRICH.For example, modulation may cause an increase or a decrease in proteinactivity, binding characteristics, or any other biological, functional,or immunological properties of TRICH.

[0131] The phrases “nucleic acid” and “nucleic acid sequence” refer to anucleotide, oligonucleotide, polynucleotide, or any fragment thereof.These phrases also refer to DNA or RNA of genomic or synthetic originwhich may be single-stranded or double-stranded and may represent thesense or the antisense strand, to peptide nucleic acid (PNA), or to anyDNA-like or RNA-like material.

[0132] “Operably linked” refers to the situation in which a firstnucleic acid sequence is placed in a functional relationship with asecond nucleic acid sequence. For instance, a promoter is operablylinked to a coding sequence if the promoter affects the transcription orexpression of the coding sequence. Operably linked DNA sequences may bein close proximity or contiguous and, where necessary to join twoprotein coding regions, in the same reading frame.

[0133] “Peptide nucleic acid” (PNA) refers to an antisense molecule oranti-gene agent which comprises an oligonucleotide of at least about 5nucleotides in length linked to a peptide backbone of amino acidresidues ending in lysine. The terminal lysine confers solubility to thecomposition. PNAs preferentially bind complementary single stranded DNAor RNA and stop transcript elongation, and may be pegylated to extendtheir lifespan in the cell.

[0134] “Post-translational modification” of an TRICH-may involvelipidation, glycosylation, phosphorylation, acetylation, racemization,proteolytic cleavage, and other modifications known in the art. Theseprocesses may occur synthetically or biochemically. Biochemicalmodifications will vary by cell type depending on the enzymatic milieuof TRICH.

[0135] “Probe” refers to nucleic acid sequences encoding TRICH, theircomplements, or fragments thereof, which are used to detect identical,allelic or related nucleic acid sequences. Probes are isolatedoligonucleotides or polynucleotides attached to a detectable label orreporter molecule. Typical labels include radioactive isotopes, ligands,chemiluminescent agents, and enzymes. “Primers” are short nucleic acids,usually DNA oligonucleotides, which may be annealed to a targetpolynucleotide by complementary base-pairing. The primer may then beextended along the target DNA strand by a DNA polymerase enzyme. Primerpairs can be used for amplification (and identification) of a nucleicacid sequence, e.g., by the polymerase chain reaction (PCR).

[0136] Probes and primers as used in the present invention typicallycomprise at least 15 contiguous nucleotides of a known sequence. Inorder to enhance specificity, longer probes and primers may also beemployed, such as probes and primers that comprise at least 20, 25, 30,40, 50, 60, 70, 80, 90, 100, or at least 150 consecutive nucleotides ofthe disclosed nucleic acid sequences. Probes and primers may beconsiderably longer than these examples, and it is understood that anylength supported by the specification, including the tables, figures,and Sequence Listing, may be used.

[0137] Methods for preparing and using probes and primers are describedin the references, for example Sambrook J. et al. (1989) MolecularCloning: A Laboratory Manual, 2^(nd) ed., vol. 1-3, Cold Spring HarborPress, Plainview N.Y.; Ausubel, F. M. et al. (1987) Current Protocols inMolecular Biology, Greene Publ. Assoc. & Wiley-Intersciences, New YorkN.Y.; Innis, M. et al. (1990) PCR Protocols. A Guide to Methods andApplications, Academic Press, San Diego Calif. PCR primer pairs can bederived from a known sequence, for example, by using computer programsintended for that purpose such as Primer (Version 0.5, 1991, WhiteheadInstitute for Biomedical Research, Cambridge Mass.).

[0138] Oligonucleotides for use as primers are selected using softwareknown in the art for such purpose. For example, OLIGO 4.06 software isuseful for the selection of PCR primer pairs of up to 100 nucleotideseach, and for the analysis of oligonucleotides and largerpolynucleotides of up to 5,000 nucleotides from an input polynucleotidesequence of up to 32 kilobases. Similar primer selection programs haveincorporated additional features for expanded capabilities. For example,the PrimOU primer selection program (available to the public from theGenome Center at University of Texas South West Medical Center, DallasTex.) is capable of choosing specific primers from megabase sequencesand is thus useful for designing primers on a genome-wide scope. ThePrimer3 primer selection program (available to the public from theWhitehead Institute/MIT Center for Genome Research, Cambridge Mass.)allows the user to input a “mispriming library,” in which sequences toavoid as primer binding sites are user-specified. Primer3 is useful, inparticular, for the selection of oligonucleotides for microarrays. (Thesource code for the latter two primer selection programs may also beobtained from their respective sources and modified to meet the user'sspecific needs.) The PrimeGen program (available to the public from theUK Human Genome Mapping Project Resource Centre, Cambridge UK) designsprimers based on multiple sequence alignments, thereby allowingselection of primers that hybridize to either the most conserved orleast conserved regions of aligned nucleic acid sequences. Hence, thisprogram is useful for identification of both unique and conservedoligonucleotides and polynucleotide fragments. The oligonucleotides andpolynucleotide fragments identified by any of the above selectionmethods are useful in hybridization technologies, for example, as PCR orsequencing primers, microarray elements, or specific probes to identifyfully or partially complementary polynucleotides in a sample of nucleicacids. Methods of oligonucleotide selection are not limited to thosedescribed above.

[0139] A “recombinant nucleic acid” is a sequence that is not naturallyoccurring or has a sequence that is made by an artificial combination oftwo or more otherwise separated segments of sequence. This artificialcombination is often accomplished by chemical synthesis or, morecommonly, by the artificial manipulation of isolated segments of nucleicacids, e.g., by genetic engineering techniques such as those describedin Sambrook, supra. The term recombinant includes nucleic acids thathave been altered solely by addition, substitution, or deletion of aportion of the nucleic acid. Frequently, a recombinant nucleic acid mayinclude a nucleic acid sequence operably linked to a promoter sequence.Such a recombinant nucleic acid may be part of a vector that is used,for example, to transform a cell.

[0140] Alternatively, such recombinant nucleic acids may be part of aviral vector, e.g., based on a vaccinia virus, that could be use tovaccinate a mammal wherein the recombinant nucleic acid is expressed,inducing a protective immunological response in the mammal.

[0141] A “regulatory element” refers to a nucleic acid sequence usuallyderived from untranslated regions of a gene and includes enhancers,promoters, introns, and 5′ and 3′ untranslated regions (UTRs).Regulatory elements interact with host or viral proteins which controltranscription, translation, or RNA stability.

[0142] “Reporter molecules” are chemical or biochemical moieties usedfor labeling a nucleic acid, amino acid, or antibody. Reporter moleculesinclude radionuclides; enzymes; fluorescent, chemiluminescent, orchromogenic agents; substrates; cofactors; inhibitors; magneticparticles; and other moieties known in the art.

[0143] An “RNA equivalent,” in reference to a DNA sequence, is composedof the same linear sequence of nucleotides as the reference DNA sequencewith the exception that all occurrences of the nitrogenous base thymineare replaced with uracil, and the sugar backbone is composed of riboseinstead of deoxyribose.

[0144] The term “sample” is used in its broadest sense. A samplesuspected of containing TRICH, nucleic acids encoding TRICH, orfragments thereof may comprise a bodily fluid; an extract from a cell,chromosome, organelle, or membrane isolated from a cell; a cell; genomicDNA, RNA, or cDNA,, in solution or bound to a substrate; a tissue; atissue print; etc.

[0145] The terms “specific binding” and “specifically binding” refer tothat interaction between a protein or peptide and an agonist, anantibody, an antagonist, a small molecule, or any natural or syntheticbinding composition. The interaction is dependent upon the presence of aparticular structure of the protein, e.g., the antigenic determinant orepitope, recognized by the binding molecule. For example, if an antibodyis specific for epitope “A,” the presence of a polypeptide comprisingthe epitope A, or the presence of free unlabeled A, in a reactioncontaining free labeled A and the antibody will reduce the amount oflabeled A that binds to the antibody.

[0146] The term “substantially purified” refers to nucleic acid or aminoacid sequences that are removed from their natural environment and areisolated or separated, and are at least 60% free, preferably at least75% free, and most preferably at least 90% free from other componentswith which they are naturally associated.

[0147] A “substitution” refers to the replacement of one or more aminoacid residues or nucleotides by different amino acid residues ornucleotides, respectively.

[0148] “Substrate” refers to any suitable rigid or semi-rigid supportincluding membranes, filters, chips, slides, wafers, fibers, magnetic ornonmagnetic beads, gels, tubing, plates, polymers, microparticles andcapillaries. The substrate can have a variety of surface forms, such aswells, trenches, pins, channels and pores, to which polynucleotides orpolypeptides are bound.

[0149] A “transcript image” refers to the collective pattern of geneexpression by a particular cell type or tissue under given conditions ata given time.

[0150] “Transformation” describes a process by which exogenous DNA isintroduced into a recipient cell. Transformation may occur under naturalor artificial conditions according to various methods well known in theart, and may rely on any known method for the insertion of foreignnucleic acid sequences into a prokaryotic or eukaryotic host cell. Themethod for transformation is selected based on the type of host cellbeing transformed and may include, but is not limited to, bacteriophageor viral infection, electroporation, heat shock, lipofection, andparticle bombardment The term “transformed cells” includes stablytransformed cells in which the inserted DNA is capable of replicationeither as an autonomously replicating plasmid or as part of the hostchromosome, as well as transiently transformed cells which express theinserted DNA or RNA for limited periods of time.

[0151] A “transgenic organism,” as used herein, is any organism,including but not limited to animals and plants, in which one or more ofthe cells of the organism contains heterologous nucleic acid introducedby way of human intervention, such as by transgenic techniques wellknown in the art. The nucleic acid is introduced into the cell, directlyor indirectly by introduction into a precursor of the cell, by way ofdeliberate genetic manipulation, such as by microinjection or byinfection with a recombinant virus. The term genetic manipulation doesnot include classical cross-breeding, or in vitro fertilization, butrather is directed to the introduction of a recombinant DNA molecule.The transgenic organisms contemplated in accordance with the presentinvention include bacteria, cyanobacteria, fungi, plants and animals.The isolated DNA of the present invention can be introduced into thehost by methods known in the art, for example infection, transfection,transformation or transconjugation. Techniques for transferring the DNAof the present invention into such organisms are widely known andprovided in references such as Sambrook et al. (1989), supra.

[0152] A “variant” of a particular nucleic acid sequence is defined as anucleic acid sequence having at least 40% sequence identity to theparticular nucleic acid sequence over a certain length of one of thenucleic acid sequences using blastn with the “BLAST 2 Sequences” toolVersion 2.0.9 (May 07, 1999) set at default parameters. Such a pair ofnucleic acids may show, for example, at least 50%, at least 60%, atleast 70%, at least 80%, at least 85%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, or at least 99% or greater sequence identityover a certain defined length. A variant may be described as, forexample, an “allelic” (as defined above), “splice,” “species,” or“polymorphic” variant. A splice variant may have significant identity toa reference molecule, but will generally have a greater or lesser numberof polynucleotides due to alternative splicing of exons during mRNAprocessing. The corresponding polypeptide may possess additionalfunctional domains or lack domains that are present in the referencemolecule. Species variants are polynucleotide sequences that vary fromone species to another. The resulting polypeptides will generally havesignificant amino acid identity relative to each other. A polymorphicvariant is a variation in the polynucleotide sequence of a particulargene between individuals of a given species. Polymorphic variants alsomay encompass “single nucleotide polymorphisms” (SNPs) in which thepolynucleotide sequence varies by one nucleotide base. The presence ofSNPs may be indicative of, for example, a certain population, a diseasestate, or a propensity for a disease state.

[0153] A variant“of a particular polypeptide sequence is defined as apolypeptide sequence having at least 40% sequence identity to theparticular polypeptide sequence over a certain length of one of thepolypeptide sequences using blastp with the “BLAST 2 Sequences” toolVersion 2.0.9 (May 07, 1999) set at default parameters. Such a pair ofpolypeptides may show, for example, at least 50%, at least 60%, at least70%, at least 80%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, or at least 99% or greater sequence identity over a certain definedlength of one of the polypeptides.

[0154] The Invention

[0155] The invention is based on the discovery of new human transportersand ion channels (TRICH), the polynucleotides encoding TRICH, and theuse of these compositions for the diagnosis, treatment, or prevention oftransport, neurological, muscle, immunological, and cell proliferativedisorders.

[0156] Table 1 summarizes the nomenclature for the full lengthpolynucleotide and polypeptide sequences of the invention. Eachpolynucleotide and its corresponding polypeptide are correlated to asingle Incyte project identification number (Incyte Project ID). Eachpolypeptide sequence is denoted by both a polypeptide sequenceidentification number (Polypeptide SEQ ID NO:) and an Incyte polypeptidesequence number (Incyte Polypeptide ID) as shown. Each polynucleotidesequence is denoted by both a polynucleotide sequence identificationnumber (Polynucleotide SEQ ID NO:) and an Incyte polynucleotideconsensus sequence number (Incyte Polynucleotide ID) as shown.

[0157] Table 2 shows sequences with homology to the polypeptides of theinvention as identified by BLAST analysis against the GenBank protein(genpept) database. Columns 1 and 2 show the polypeptide sequenceidentification number (Polypeptide SEQ ID NO:) and the correspondingIncyte polypeptide sequence number (Incyte Polypeptide ID) forpolypeptides of the invention. Column 3 shows the GenBank identificationnumber (Genbank ID NO:) of the nearest GenBank homolog. Column 4 showsthe probability score for the match between each polypeptide and itsGenBank homolog. Column 5 shows the annotation of the GenBank homologalong with relevant citations where applicable, all of which areexpressly incorporated by reference herein.

[0158] Table 3 shows various structural features of the polypeptides ofthe invention. Columns 1 and 2 show the polypeptide sequenceidentification number (SEQ ID NO:) and the corresponding Incytepolypeptide sequence number (Incyte Polypeptide ID) for each polypeptideof the invention. Column 3 shows the number of amino acid residues ineach polypeptide. Column 4 shows potential phosphorylation sites, andcolumn 5 shows potential glycosylation sites, as determined by theMOTIFS program of the GCG sequence analysis software package (GeneticsComputer Group, Madison Wis.). Column 6 shows amino acid residuescomprising signature sequences, domains, and motifs. Column 7 showsanalytical methods for protein structure/function analysis and in somecases, searchable databases to which the analytical methods wereapplied.

[0159] Together, Tables 2 and 3 summarize the properties of polypeptidesof the invention, and these properties establish that the claimedpolypeptides are transporters and ion channels. For example, SEQ ID NO:1 is 88% identical to rat ABC transporter (GenBank ID g2982567) asdetermined by the Basic Local Alignment Search Tool (BLAST). (See Table2.) The BLAST probability score is 0.0 (scores are rounded down to zeroif they are extremely small, e.g. less than 10⁻³⁰⁰), which indicates theprobability of obtaining the observed polypeptide sequence alignment bychance. SEQ ID NO: 1 also contains an ABC transporter active site domainand transmembrane domain as determined by searching for statisticallysignificant matches in the hidden Markov model (HMM)-based PFAM databaseof conserved protein family domains. (See Table 3.) Results from BLIMPS,MOTIFS, and PROFILESCAN analyses provide further corroborative evidencethat SEQ ID NO: 1 is an ABC transporter. In an alternative example, SEQID NO: 4 is 87% identical to human mitochondrial ornithine transporter(GenBank ID g5565862) as determined by the Basic Local Alignment SearchTool (BLAST). (See Table 2.) The BLAST probability score is 8.1e-141,which indicates the probability of obtaining the observed polypeptidesequence alignment by chance. SEQ ID NO: 4 also contains a mitochondrialcarrier proteins domain as determined by searching for statisticallysignificant matches in the hidden Markov model (HMM)-based PFAM databaseof conserved protein family domains. (See Table 3.) Data from BLIMPS,MOTIFS, and PROFILESCAN analyses provide further corroborative evidencethat SEQ ID NO: 4 is a mitochondrial carrier protein. In an alternativeexample, SEQ ID NO: 8 is 88% identical to rat peptide/histidinetransporter (GenBank ID g2208839) as determined by the Basic LocalAlignment Search Tool (BLAST). (See Table 2.) The BLAST probabilityscore is 1.8e-262, which indicates the probability of obtaining theobserved polypeptide sequence alignment by chance. SEQ ID NO: 8 alsocontains a PTR2 proton-dependent oligopeptide transport (POT) familypeptide transporter signature as determined by searching forstatistically significant matches in the hidden Markov model (HMM)-basedPFAM database of conserved protein family domains. (See Table 3.) Datafrom BLAST-DOMO, BLAST-PRODOM, BLIMPS, and MOTIFS analyses providefurther corroborative evidence that SEQ ID NO: 8 is a transmembrane PTR2POT family transporter. In an alternative example, SEQ ID NO: 15 is 51%identical from amino acid residues 117 to 742 to rat sodium/glucosecotransporter (GenBank ID g286259) as determined by the Basic LocalAlignment Search Tool (BLAST). (See Table 2.) The BLAST probabilityscore is 8.9e-174, which indicates the probability of obtaining theobserved polypeptide sequence alignment by chance. SEQ ID NO: 15 alsocontains a sodium:solute symporter family domain as determined bysearching for statistically significant matches in the hidden Markovmodel (HMM)-based PFAM database of conserved protein family domains.(See Table 3.) Data from BLIMPS, MOTIFS, and PROFILESCAN analysesprovide further corroborative evidence that SEQ ID NO: 15 is asodium/glucose cotransporter. In an alternative example, SEQ ID NO: 18is 94% identical from amino acids 300 to 1771 to mouse ATP-bindingcassette 2 transporter (GenBank ID g495259) as determined by the BasicLocal Alignment Search Tool (BLAST). (See Table 2.) The BLASTprobability score is 0.0, which indicates the probability of obtainingthe observed polypeptide sequence alignment by chance. SEQ ID NO: 18also contains an ABC transporter domain as determined by searching forstatistically significant matches in the hidden Markov model (HMM)-basedPFAM database of conserved protein family domains. (See Table 3.) Datafrom MOTIFS, and PROFILESCAN analyses provide further corroborativeevidence that SEQ ID NO: 18 is an ABC transporter. SEQ ID NO: 2, SEQ IDNO: 3, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 9, SEQ IDNO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQID NO: 16, SEQ ID NO: 17, SEQ I) NO: 19, SEQ ID NO: 20, SEQ ID NO: 21,SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO:26, and SEQ ID NO: 27 were analyzed and annotated in a similar manner.The algorithms and parameters for the analysis of SEQ ID NO: 1-27 aredescribed in Table 7.

[0160] As shown in Table 4, the full length polynucleotide sequences ofthe present invention were assembled using cDNA sequences or coding(exon) sequences derived from genomic DNA, or any combination of thesetwo types of sequences. Columns 1 and 2 list the polynucleotide sequenceidentification number (Polynucleotide SEQ ID NO:) and the correspondingIncyte polynucleotide consensus sequence number (Incyte PolynucleotideID) for each polynucleotide of the invention. Column 3 shows the lengthof each polynucleotide sequence in basepairs. Column 4 lists fragmentsof the polynucleotide sequences which are useful, for example, inhybridization or amplification technologies that identify SEQ ID NO:28-54 or that distinguish between SEQ ID NO: 28-54 and relatedpolynucleotide sequences. Column 5 shows identification numberscorresponding to cDNA sequences, coding sequences (exons) predicted fromgenomic DNA, and/or sequence assemblages comprised of both cDNA andgenomic DNA. These sequences were used to assemble the full lengthpolynucleotide sequences of the invention. Columns 6 and 7 of Table 4show the nucleotide start (5′) and stop (3′) positions of the cDNAand/or genomic sequences in column 5 relative to their respective fulllength sequences.

[0161] The identification numbers in Column 5 of Table 4 may referspecifically, for example, to Incyte cDNAs along with theircorresponding cDNA libraries. For example, 7249756H2 is theidentification number of an Incyte cDNA sequence, and PROSTMY01 is thecDNA library from which it is derived. Incyte cDNAs for which cDNAlibraries are not indicated were derived from pooled cDNA libraries(e.g., 71753989V1). Alternatively, the identification numbers in column5 may refer to GenBank cDNAs or ESTs (e.g., g7457275) which contributedto the assembly of the full length polynucleotide sequences.Alternatively, the identification numbers in column 5 may refer tocoding regions predicted by Genscan analysis of genomic DNA. Forexample, GNN.g7160536_(—)000034_(—)002 is the identification number of aGenscan-predicted coding sequence, with g7160536 being the GenBankidentification number of the sequence to which Genscan was applied. TheGenscan-predicted coding sequences may have been edited prior toassembly. (See Example IV.) Alternatively, the identification numbers incolumn 5 may refer to assemblages of both cDNA and Genscan-predictedexons brought together by an “exon stitching” algorithm. For example,FL180719_(—)00001 represents a “stitched” sequence in which 180719 isthe identification number of the cluster of sequences to which thealgorithm was applied, and 00001 is the number of the predictiongenerated by the algorithm. (See Example V.) Alternatively, theidentification numbers in column 5 may refer to assemblages of both cDNAand Genscan-predicted exons brought together by an “exon-stretching”algorithm. For example, FL7472537_g5815493_g7406950 is theidentification number of a “stretched” sequence, with 7472537 being theIncyte project identification number, g5815493 being the GenBankidentification number of the human genomic sequence to which the“exon-stretching” algorithm was applied, and g7406950 being the GenBankidentification number of the nearest GenBank protein homolog. (SeeExample V.) In some cases, Incyte cDNA coverage redundant with thesequence coverage shown in column 5 was obtained to confirm the finalconsensus polynucleotide sequence, but the relevant Incyte cDNAidentification numbers are not shown.

[0162] Table 5 shows the representative cDNA libraries for those fulllength polynucleotide sequences which were assembled using Incyte cDNAsequences. The representative cDNA library is the Incyte cDNA librarywhich is most frequently represented by the Incyte cDNA sequences whichwere used to assemble and confirm the above polynucleotide sequences.The tissues and vectors which were used to construct the cDNA librariesshown in Table 5 are described in Table 6.

[0163] The invention also encompasses TRICH variants. A preferred TRICHvariant is one which has at least about 80%, or alternatively at leastabout 90%, or even at least about 95% amino acid sequence identity tothe TRICH amino acid sequence, and which contains at least onefunctional or structural characteristic of TRICH.

[0164] The invention also encompasses polynucleotides which encodeTRICH. In a particular embodiment, the invention encompasses apolynucleotide sequence comprising a sequence selected from the groupconsisting of SEQ ID NO: 28-54, which encodes TRICH. The polynucleotidesequences of SEQ ID NO: 28-54, as presented in the Sequence Listing,embrace the equivalent RNA sequences, wherein occurrences of thenitrogenous base thymine are replaced with uracil, and the sugarbackbone is composed of ribose instead of deoxyribose.

[0165] The invention also encompasses a variant of a polynucleotidesequence encoding TRICH. In particular, such a variant polynucleotidesequence will have at least about 70%, or alternatively at least about85%, or even at least about 95% polynucleotide sequence identity to thepolynuclectide sequence encoding TRICH. A particular aspect of theinvention encompasses a variant of a polynucleotide sequence comprisinga sequence selected from the group consisting of SEQ ID NO: 28-54 whichhas at least about 70%, or alternatively at least about 85%, or even atleast about 95% polynucleotide sequence identity to a nucleic acidsequence selected from the group consisting of SEQ ID NO: 28-54. Any oneof the polynucleotide variants described above can encode an amino acidsequence which contains at least one functional or structuralcharacteristic of TRICH.

[0166] It will be appreciated by those skilled in the art that as aresult of the degeneracy of the genetic code, a multitude ofpolynucleotide sequences encoding TRICH, some bearing minimal similarityto the polynucleotide sequences of any known and naturally occurringgene, may be produced. Thus, the invention contemplates each and everypossible variation of polynucleotide sequence that could be made byselecting combinations based on possible codon choices. Thesecombinations are made in accordance with the standard triplet geneticcode as applied to the polynucleotide sequence of naturally occurringTRICH, and all such variations are to be considered as beingspecifically disclosed.

[0167] Although nucleotide sequences which encode TRICH and its variantsare generally capable of hybridizing to the nucleotide sequence of thenaturally occurring TRICH under appropriately selected conditions ofstringency, it may be advantageous to produce nucleotide sequencesencoding TRICH or its derivatives possessing a substantially differentcodon usage, e.g., inclusion of non-naturally occurring codons. Codonsmay be selected to increase the rate at which expression of the peptideoccurs in a particular prokaryotic or eukaryotic host in accordance withthe frequency with which particular codons are utilized by the host.Other reasons for substantially altering the nucleotide sequenceencoding TRICH and its derivatives without altering the encoded aminoacid sequences include the production of RNA transcripts having moredesirable properties, such as a greater half-life, than transcriptsproduced from the naturally occurring sequence.

[0168] The invention also encompasses production of DNA sequences whichencode TRICH and TRICH derivatives, or fragments thereof, entirely bysynthetic chemistry. After production, the synthetic sequence may beinserted into any of the many available expression vectors and cellsystems using reagents well known in the art. Moreover, syntheticchemistry may be used to introduce mutations into a sequence encodingTRICH or any fragment thereof.

[0169] Also encompassed by the invention are polynucleotide sequencesthat are capable of hybridizing to the claimed polynucleotide sequences,and, in particular, to those shown in SEQ ID NO: 28-54 and fragmentsthereof under various conditions of stringency. (See, e.g., Wahl, G. M.and S. L Berger (1987) Methods Enzymol. 152:399-407; Kimmel, A. R.(1987) Methods Enzymol. 152:507-511.) Hybridization conditions,including annealing and wash conditions, are described in Definitions.”

[0170] Methods for DNA sequencing are well known in the art and may beused to practice any of the embodiments of the invention. The methodsmay employ such enzymes as the Klenow fragment of DNA polymerase I,SEQUENASE (US Biochemical, Cleveland Ohio), Taq polymerase (AppliedBiosystems), thermostable T7 polymerase (Amersham Pharmacia Biotech,Piscataway N.J.), or combinations of polymerases and proofreadingexonucleases such as those found in the ELONGASE amplification system(Life Technologies, Gaithersburg Md.). Preferably, sequence preparationis automated with machines such as the MICROLAB 2200 liquid transfersystem (Hamilton, Reno Nev.), PTC200 thermal cycler (MJ Research,Watertown Mass.) and ABI CATALYST 800 thermal cycler (AppliedBiosystems). Sequencing is then carried out using either the ABI 373 or377 DNA sequencing system (Applied Biosystems), the MEGABACE 1000 DNAsequencing system (Molecular Dynamics, Sunnyvale Calif.), or othersystems known in the art. The resulting sequences are analyzed using avariety of algorithms which are well known in the art. (See, e.g.,Ausubel, F. M. (1997) Short Protocols in Molecular Biology, John Wiley &Sons, New York N.Y., unit 7.7; Meyers, R. A. (1995) Molecular Biologyand Biotechnology, Wiley VCH, New York N.Y., pp.856-853.)

[0171] The nucleic acid sequences encoding TRICH may be extendedutilizing a partial nucleotide sequence and employing various PCR-basedmethods known in the art to detect upstream sequences, such as promotersand regulatory elements. For example, one method which may be employed,restriction-site PCR, uses universal and nested primers to amplifyunknown sequence from genomic DNA within a cloning vector. (See, e.g.,Sarkar, G. (1993) PCR Methods Applic. 2:318-322.) Another method,inverse PCR, uses primers that extend in divergent directions to amplifyunknown sequence from a circularized template. The template is derivedfrom restriction fragments comprising a known genomic locus andsurrounding sequences. (See, e.g., Triglia, T. et al. (1988) NucleicAcids Res. 16:8186.) A third method, capture PCR, involves PCRamplification of DNA fragments adjacent to known sequences in human andyeast artificial chromosome DNA. (See, e.g., Lagerstrom, M. et al;(1991) PCR Methods Applic. 1:111-119.) In this method, multiplerestriction enzyme digestions and ligations may be used to insert anengineered double-stranded sequence into a region of unknown sequencebefore performing PCR. Other methods which may be used to retrieveunknown sequences are known in the art. (See, e.g., Parker, J. D. et al.(1991) Nucleic Acids Res. 19:3055-3060). Additionally, one may use PCR,nested primers, and PROMOTERFINDER libraries (Clontech, Palo AltoCalif.) to walk genomic DNA. This procedure avoids the need to screenlibraries and is useful in finding intron/exon junctions. For allPCR-based methods, primers maybe designed using commercially availablesoftware, such as OLIGO 4.06 primer analysis software (NationalBiosciences, Plymouth Minn.) or another appropriate program, to be about22 to 30 nucleotides in length. to have a GC content of about 50% ormore, and to anneal to the template at temperatures of about 68° C. to72° C.

[0172] When screening for full length cDNAs, it is preferable to uselibraries that have been size-selected to include larger cDNAs. Inaddition, random-primed libraries, which often include sequencescontaining the 5′ regions of genes, are preferable for situations inwhich an oligo d(T) library does not yield a full-length cDNA. Genomiclibraries may be useful for extension of sequence into 5′non-transcribed regulatory regions.

[0173] Capillary electrophoresis systems which are commerciallyavailable may be used to analyze the size or confirm the nucleotidesequence of sequencing or PCR products. In particular, capillarysequencing may employ flowable polymers for electrophoretic separation,four different nucleotide-specific, laser-stimulated fluorescent dyes,and a charge coupled device camera for detection of the emittedwavelengths. Output/light intensity may be converted to electricalsignal using appropriate software (e.g., GENOTYPER and SEQUENCENAVIGATOR, Applied Biosystems), and the entire process from loading ofsamples to computer analysis and electronic data display may be computercontrolled. Capillary electrophoresis is especially preferable forsequencing small DNA fragments which may be present in limited amountsin a particular sample.

[0174] In another embodiment of the invention, polynucleotide sequencesor fragments thereof which encode TRICH may be cloned in recombinant DNAmolecules that direct expression of TRICH, or fragments or functionalequivalents thereof, in appropriate host cells. Due to the inherentdegeneracy of the genetic code, other DNA sequences which encodesubstantially the same or a functionally equivalent amino acid sequencemay be produced and used to express TRICH.

[0175] The nucleotide sequences of the present invention can beengineered using methods generally known in the art in order to alterTRICH-encoding sequences for a variety of purposes including, but notlimited to, modification of the cloning, processing, and/or expressionof the gene product. DNA shuffling by random fragmentation and PCRreassembly of gene fragments and synthetic oligonucleotides may be usedto engineer the nucleotide sequences. For example,oligonucleotide-mediated site-directed mutagenesis may be used tointroduce mutations that create new restriction sites, alterglycosylation patterns, change codon preference, produce splicevariants, and so forth.

[0176] The nucleotides of the present invention may be subjected to DNAshuffling techniques such as MOLECULARBREEDING (Maxygen Inc., SantaClara Calif.; described in U.S. Pat. No. 5,837,458; Chang, C. -C. et al.(1999) Nat. Biotechnol. 17:793-797; Christians, F. C. et al. (1999) Nat.Biotechnol. 17:259-264; and Crameri, A. et al. (1996) Nat. Biotechnol.14:315-319) to alter or improve the biological properties of TRICH, suchas its biological or enzymatic activity or its ability to bind to othermolecules or compounds. DNA shuffling is a process by which a library ofgene variants is produced using PCR-mediated recombination of genefragments. The library is then subjected to selection or screeningprocedures that identify those gene variants with the desiredproperties. These preferred variants may then be pooled and furthersubjected to recursive rounds of DNA shuffling and selection/screening.Thus, genetic diversity is created through “artificial” breeding andrapid molecular evolution. For example, fragments of a single genecontaining random point mutations may be recombined, screened, and thenreshuffled until the desired properties are optimized. Alternatively,fragments of a given gene may be recombined with fragments of homologousgenes in the same gene family, either from the same or differentspecies, thereby maximizing the genetic diversity of multiple naturallyoccurring genes in a directed and controllable manner.

[0177] In another embodiment, sequences encoding TRICH may besynthesized, in whole or in part, using chemical methods well known inthe art. (See, e.g., Caruthers, M. H. et al. (1980) Nucleic Acids Symp.Ser. 7:215-223; and Horn, T. et al. (1980) Nucleic Acids Symp. Ser.7:225-232.) Alternatively, TRICH itself or a fragment thereof may besynthesized using chemical methods. For example, peptide synthesis canbe performed using various solution-phase or solid-phase techniques.(See, e.g., Creighton, T. (1984) Proteins, Structures and MolecularProperties, W H Freeman, New York N.Y., pp. 55-60; and Roberge, J. Y. etal. (1995) Science 269:202-204.) Automated synthesis may be achievedusing the ABI 431 A peptide synthesizer (Applied Biosystems).Additionally, the amino acid sequence of TRICH, or any part thereof, maybe altered during direct synthesis and/or combined with sequences fromother proteins, or any part thereof, to produce a variant polypeptide ora polypeptide having a sequence of a naturally occurring polypeptide.

[0178] The peptide may be substantially purified by preparative highperformance liquid chromatography. (See, e.g., Chiez, R. M. and F. Z.Regnier (1990) Methods Enzymol. 182:392-421.) The composition of thesynthetic peptides may be confirmed by amino acid analysis or bysequencing. (See, e.g., Creighton, supra, pp. 28-53.) In order toexpress a biologically active TRICH, the nucleotide sequences encodingTRICH or derivatives thereof may be inserted into an appropriateexpression vector, i.e., a vector which contains the necessary elementsfor transcriptional and translational control of the inserted codingsequence in a suitable host. These elements include regulatorysequences, such as enhancers, constitutive and inducible promoters, and5′ and 3′ untranslated regions in the vector and in polynucleotidesequences encoding TRICH. Such elements may vary in their strength andspecificity. Specific initiation signals may also be used to achievemore efficient translation of sequences encoding TRICH. Such signalsinclude the ATG initiation codon and adjacent sequences, e.g. the Kozaksequence. In cases where sequences encoding TRICH and its initiationcodon and upstream regulatory sequences are inserted into theappropriate expression vector, no additional transcriptional ortranslational control signals may be needed. However, in cases whereonly coding sequence, or a fragment thereof, is inserted, exogenoustranslational control signals including an in-frame ATG initiation codonshould be provided by the vector. Exogenous translational elements andinitiation codons may be of various origins, both natural and synthetic.The efficiency of expression may be enhanced by the inclusion ofenhancers appropriate for the particular host cell system used. (See,e.g., Scharf, D. et al. (1994) Results Probl. Cell Differ. 20:125-162.)

[0179] Methods which are well known to those skilled in the art may beused to construct expression vectors containing sequences encoding TRICHand appropriate transcriptional and translational control elements.These methods include in vitro recombinant DNA techniques, synthetictechniques, and in vivo genetic recombination. (See, e.g., Sambrook, J.et al. (1989) Molecular Cloning, A Laboratory Manual, Cold Spring HarborPress, Plainview N.Y., ch. 4, 8, and 16-17; Ausubel, F. M. et al. (1995)Current Protocols in Molecular Biology, John Wiley & Sons, New YorkN.Y., ch. 9, 13, and 16.)

[0180] A variety of expression vector/host systems may be utilized tocontain and express sequences encoding TRICH. These include, but are notlimited to, microorganisms such as bacteria transformed with recombinantbacteriophage, plasmid, or cosmid DNA expression vectors; yeasttransformed with yeast expression vectors; insect cell systems infectedwith viral expression vectors (e.g., baculovirus); plant cell systemstransformed with viral expression vectors (e.g., cauliflower mosaicvirus, CaMV, or tobacco mosaic virus, TMV) or with bacterial expressionvectors (e.g., Ti or pBR322 plasmids); or animal cell systems. (See,e.g., Sambrook, supra; Ausubel, supra; Van Heeke, G. and S. M. Schuster(1989) J. Biol. Chem. 264:5503-5509; Engelhard, E. K. et al. (1994)Proc. Natl. Acad. Sci. USA 91:3224-3227; Sandig, V. et al. (1996) Hum.Gene Ther. 7:1937-1945; Takamatsu, N. (1987) EMBO J. 6:307-311; TheMcGraw Hill Yearbook of Science and Technology (1992) McGraw Hill, NewYork N.Y., pp. 191-196; Logan, J. and T. Shenk (1984) Proc. Natl. Acad.Sci. USA 81:3655-3659; and Harrington, J. J. et al. (1997) Nat Genet.15:345-355.) Expression vectors derived from retroviruses, adenoviruses,or herpes or vaccinia viruses, or from various bacterial plasmids, maybe used for delivery of nucleotide sequences to the targeted organ,tissue, or cell population. (See, e.g., Di Nicola, M. et al. (1998)Cancer Gen. Ther. 5(6):350-356; Yu, M. et al. (1993) Proc. Natl. Acad.Sci. USA 90(13):6340-6344; Buller, R. M. et al. (1985) Nature317(6040):813-815; McGregor, D. P. et al. (1994) Mol. Immunol.31(3):219-226; and Verma, I. M. and N. Somia (1997) Nature 389:239-242.)The invention is not limited by the host cell employed.

[0181] In bacterial systems, a number of cloning and expression vectorsmay be selected depending upon the use intended for polynucleotidesequences encoding TRICH. For example, routine cloning, subcloning, andpropagation of polynucleotide sequences encoding TRICH can be achievedusing a multifunctional E. coli vector such as PBLUESCRIPT (Stratagene,La Jolla Calif.) or PSPORT1 plasmid (Life Technologies). Ligation ofsequences encoding TRICH into the vector's multiple cloning sitedisrupts the lacZ gene, allowing a calorimetric screening procedure foridentification of transformed bacteria containing recombinant molecules.In addition, these vectors may be useful for in vitro transcription,dideoxy sequencing, single strand rescue with helper phage, and creationof nested deletions in the cloned sequence. (See, e.g., Van Heeke, G.and S. M. Schuster (1989) J. Biol. Chem. 264:5503-5509.) When largequantities of TRICH are needed, e.g. for the production of antibodies,vectors which direct high level expression of TRICH may be used. Forexample, vectors containing the strong, inducible SP6 or T7bacteriophage promoter may be used.

[0182] Yeast expression systems may be used for production of TRICH. Anumber of vectors containing constitutive or inducible promoters, suchas alpha factor, alcohol oxidase, and PGH promoters, may be used in theyeast Saccharomyces cerevisiae or Pichia pastoris. In addition, suchvectors direct either the secretion or intracellular retention ofexpressed proteins and enable integration of foreign sequences into thehost genome for stable propagation. (See, e.g., Ausubel, 1995, supra;Bitter, G. A. et al. (1987) Methods Enzymol. 153:516-544; and Scorer, C.A. et al. (1994) Bio/Technology 12:181-184.)

[0183] Plant systems may also be used for expression of TRICH.Transcription of sequences encoding TRICH may be driven by viralpromoters, e.g., the 35S and 19S promoters of CaMV used alone or incombination with the omega leader sequence from TMV (Takamatsu, N.(1987) EMBO J. 6:307-311). Alternatively, plant promoters such as thesmall subunit of RUBISCO or heat shock promoters may be used. (See,e.g., Coruzzi, G. et al. (1984) EMBO J. 3:1671-1680; Broglie, R. et al.(1984) Science 224:838-843; and Winter, J. et al. (1991) Results ProblCell Differ. 17:85-105.) These constructs can be introduced into plantcells by direct DNA transformation or pathogen-mediated transfection.(See, e.g., The McGraw Hill Yearbook of Science and Technology (1992)McGraw Hill, New York N.Y., pp. 191-196.)

[0184] In mammalian cells, a number of viral-based expression systemsmay be utilized. In cases where an adenovirus is used as an expressionvector, sequences encoding TRICH may be ligated into an adenovirustranscription/translation complex consisting of the late promoter andtripartite leader sequence. Insertion in a non-essential E1 or E3 regionof the viral genome may be used to obtain infective virus whichexpresses TRICH in host cells. (See, e.g., Logan, J. and T. Shenk (1984)Proc. Natl. Acad. Sci. USA 81:3655-3659.) In addition, transcriptionenhancers, such as the Rous sarcoma virus (RSV) enhancer, may be used toincrease expression in mammalian host cells. SV40 or EBV-based vectorsmay also be used for high-level protein expression.

[0185] Human artificial chromosomes (HACs) may also be employed todeliver larger fragments of DNA than can be contained in and expressedfrom a plasmid. HACs of about 6 kb to 10 Mb are constructed anddelivered via conventional delivery methods (liposomes, polycationicamino polymers, or vesicles) for therapeutic purposes. (See, e.g.,Harrington, J. J. et al. (1997) Nat. Genet. 15:345-355.)

[0186] For long term production of recombinant proteins in mammaliansystems, stable expression of TRICH in cell lines is preferred. Forexample, sequences encoding TRICH can be transformed into cell linesusing expression vectors which may contain viral origins of replicationand/or endogenous expression elements and a selectable marker gene onthe same or on a separate vector. Following the introduction of thevector, cells may be allowed to grow for about 1 to 2 days in enrichedmedia before being switched to selective media. The purpose of theselectable marker is to confer resistance to a selective agent, and itspresence allows growth and recovery of cells which successfully expressthe introduced sequences. Resistant clones of stably transformed cellsmay be propagated using tissue culture techniques appropriate to thecell type.

[0187] Any number of selection systems may be used to recovertransformed cell lines. These include, but are not limited to, theherpes simplex virus thymidine kinase and adeninephosphoribosyltransferase genes, for use in tk⁻ and apr⁻ cells,respectively. (See, e.g., Wigler, M. et al. (1977) Cell 11:223-232;Lowy, I. et al. (1980) Cell 22:817-823.) Also, antimetabolite,antibiotic, or herbicide resistance can be used as the basis forselection. For example, dhfr confers resistance to methotrexate; neoconfers resistance to the aminoglycosides neomycin and G-418; and alsand pat confer resistance to chlorsulfuron and phosphinotricinacetyltransferase, respectively. (See, e.g., Wigler, M. et al. (1980)Proc. Natl. Acad. Sci. USA 77:3567-3570; Colbere-Garapin, F. et al.(1981) J. Mol. Biol. 150:1-14.) Additional selectable genes have beendescribed, e.g., trpB and hisD, which alter cellular requirements formetabolites. (See, e.g., Hartman, S. C. and R. C. Mulligan (1988) Proc.Natl. Acad. Sci. USA 85:8047-8051.) Visible markers, e.g., anthocyanins,green fluorescent proteins (GFP; Clontech), β glucuronidase and itssubstrate β-glucuronide, or luciferase and its substrate luciferin maybe used. These markers can be used not only to identify transformants,but also to quantify the amount of transient or stable proteinexpression attributable to a specific vector system. (See, e.g., Rhodes,C. A. (1995) Methods Mol. Biol. 55:121-131.)

[0188] Although the presence/absence of marker gene expression suggeststhat the gene of interest is also present, the presence and expressionof the gene may need to be confirmed. For example, if the sequenceencoding TRICH is inserted within a marker gene sequence, transformedcells containing sequences encoding TRICH can be identified by theabsence of marker gene function. Alternatively, a marker gene can beplaced in tandem with a sequence encoding TRICH under the control of asingle promoter. Expression of the marker gene in response to inductionor selection usually indicates expression of the tandem gene as well.

[0189] In general, host cells that contain the nucleic acid sequenceencoding TRICH and that express TRICH may be identified by a variety ofprocedures known to those of skill in the art. These procedures include,but are not limited to, DNA-DNA or DNA-RNA hybridizations, PCRamplification, and protein bioassay or immunoassay techniques whichinclude membrane, solution, or chip based technologies for the detectionand/or quantification of nucleic acid or protein sequences.

[0190] Immunological methods for detecting and measuring the expressionof TRICH using either specific polyclonal or monoclonal antibodies areknown in the art. Examples of such techniques include enzyme-linkedimmunosorbent assays (ELISAs), radioimmunoassays (RIAs), andfluorescence activated cell sorting (FACS). A two-site, monoclonal-basedimmunoassay utilizing monoclonal antibodies reactive to twonon-interfering epitopes on TRICH is preferred, but a competitivebinding assay may be employed. These and other assays are well known inthe art. (See, e.g., Hampton, R. et al. (1990) Serological Methods, aLaboratory Manual, APS Press, St. Paul Minn., Sect. IV; Coligan, J. E.et al. (1997) Current Protocols in Immunology, Greene Pub. Associatesand Wiley-Interscience, New York N.Y.; and Pound, J. D. (1998)Immunochemical Protocols, Humana Press, Totowa N.J.)

[0191] A wide variety of labels and conjugation techniques are known bythose skilled in the art and may be used in various nucleic acid andamino acid assays. Means for producing labeled hybridization or PCRprobes for detecting sequences related to polynucleotides encoding TRICHinclude oligolabeling, nick translation, end-labeling, or PCRamplification using a labeled nucleotide. Alternatively, the sequencesencoding TRICH, or any fragments thereof, may be cloned into a vectorfor the production of an mRNA probe. Such vectors are known in the art,are commercially available, and may be used to synthesize RNA probes invitro by addition of an appropriate RNA polymerase such as T7, T3, orSP6 and labeled nucleotides. These procedures may be conducted using avariety of commercially available kits, such as those provided byAmersham Pharmacia Biotech, Promega (Madison Wis.), and US Biochemical.Suitable reporter molecules or labels which may be used for ease ofdetection include radionuclides, enzymes, fluorescent, chemiluminescent,or chromogenic agents, as well as substrates, cofactors, inhibitors,magnetic particles, and the like.

[0192] Host cells transformed with nucleotide sequences encoding TRICHmay be cultured under conditions suitable for the expression andrecovery of the protein from cell culture. The protein produced by atransformed cell may be secreted or retained intracellularly dependingon the sequence and/or the vector used. As will be understood by thoseof skill in the art, expression vectors containing polynucleotides whichencode TRICH may be designed to contain signal sequences which directsecretion of TRICH through a prokaryotic or eukaryotic cell membrane.

[0193] In addition, a host cell strain may be chosen for its ability tomodulate expression of the inserted sequences or to process theexpressed protein in the desired fashion. Such modifications of thepolypeptide include, but are not limited to, acetylation, carboxylation,glycosylation, phosphorylation, lipidation, and acylation.Post-translational processing which cleaves a “prepro” or “pro” form ofthe protein may also be used to specify protein targeting, folding,and/or activity. Different host cells which have specific cellularmachinery and characteristic mechanisms for post-translationalactivities (e.g., CHO, HeLa, MDCK, HEK293, and WI38) are available fromthe American Type Culture Collection (ATCC, Manassas Va.) and may bechosen to ensure the correct modification and processing of the foreignprotein.

[0194] In another embodiment of the invention, natural, modified, orrecombinant nucleic acid sequences encoding TRICH may be ligated to aheterologous sequence resulting in translation of a fusion protein inany of the aforementioned host systems. For example, a chimeric TRICHprotein containing a heterologous moiety that can be recognized by acommercially available antibody may facilitate the screening of peptidelibraries for inhibitors of TRICH activity. Heterologous protein andpeptide moieties may also facilitate purification of fusion proteinsusing commercially available affinity matrices. Such moieties include,but are not limited to, glutathione S-transferase (GST), maltose bindingprotein (MBP), thioredoxin (Trx), calmodulin binding peptide (CBP),6-His, FLAG, c-myc, and hemagglutinin (HA). GST, MBP, Trx, CBP, and6-His enable purification of their cognate fusion proteins onimmobilized glutathione, maltose, phenylarsine oxide, calmodulin, andmetal-chelate resins, respectively. FLAG, c-myc, and hemagglutinin (HA)enable immunoaffinity purification of fusion proteins using commerciallyavailable monoclonal and polyclonal antibodies that specificallyrecognize these epitope tags. A fusion protein may also be engineered tocontain a proteolytic cleavage site located between the TRICH encodingsequence and the heterologous protein sequence, so that TRICH may becleaved away from the heterologous moiety following purification.Methods for fusion protein expression and purification are discussed inAusubel (1995, supra, ch. 10). A variety of commercially available kitsmay also be used to facilitate expression and purification of fusionproteins.

[0195] In a further embodiment of the invention, synthesis ofradiolabeled TRICH may be achieved in vitro using the TNT rabbitreticulocyte lysate or wheat germ extract system (Promega). Thesesystems couple transcription and translation of protein-coding sequencesoperably associated with the T7, T3, or SP6 promoters. Translation takesplace in the presence of a radiolabeled amino acid precursor, forexample, ³⁵S-methionine.

[0196] TRICH of the present invention or fragments thereof may be usedto screen for compounds that specifically bind to TRICH. At least oneand up to a plurality of test compounds may be screened for specificbinding to TRICH. Examples of test compounds include antibodies,oligonucleotides, proteins (e.g., receptors), or small molecules.

[0197] In one embodiment, the compound thus identified is closelyrelated to the natural ligand of TRICH, e.g., a ligand or fragmentthereof, a natural substrate, a structural or functional mimetic, or anatural binding partner. (See, e.g., Coligan, J. E. et al. (1991)Current Protocols Immunology 1(2): Chapter 5.) Similarly, the compoundcan be closely related to the natural receptor to which TRICH binds, orto at least a fragment of the receptor, e.g., the ligand binding site.In either case, the compound can be rationally designed using knowntechniques. In one embodiment, screening for these compounds involvesproducing appropriate cells which express TRICH, either as a secretedprotein or on the cell membrane. Preferred cells include cells frommammals, yeast, Drosophila, or E. coli. Cells expressing TRICH or cellmembrane fractions which contain TRICH are then contacted with a testcompound and binding, stimulation, or inhibition of activity of eitherTRICH or the compound is analyzed.

[0198] An assay may simply test binding of a test compound to thepolypeptide, wherein binding is detected by a fluorophore, radioisotope,enzyme conjugate, or other detectable label. For example, the assay maycomprise the steps of combining at least one test compound with TRICH,either in solution or affixed to a solid support, and detecting thebinding of TRICH to the compound. Alternatively, the assay may detect ormeasure binding of a test compound in the presence of a labeledcompetitor. Additionally, the assay may be carried out using cell-freepreparations, chemical libraries, or natural product mixtures, and thetest compound(s) may be free in solution or affixed to a solid support.

[0199] TRICH of the present invention or fragments thereof may be usedto screen for compounds that modulate the activity of TRICH. Suchcompounds may include agonists, antagonists, or partial or inverseagonists. In one embodiment, an assay is performed under conditionspermissive for TRICH activity, wherein TRICH is combined with at leastone test compound, and the activity of TRICH in the presence of a testcompound is compared with the activity of TRICH in the absence of thetest compound. A change in the activity of TRICH in the presence of thetest compound is indicative of a compound that modulates the activity ofTRICH. Alternatively, a test compound is combined with an in vitro orcell-free system comprising TRICH under conditions suitable for TRICHactivity, and the assay is performed. In either of these assays, a testcompound which modulates the activity of TRICH may do so indirectly andneed not come in direct contact with the test compound. At least one andup to a plurality of test compounds may be screened.

[0200] In another embodiment, polynucleotides encoding TRICH or theirmammalian homologs may be “knocked out” in an animal model system usinghomologous recombination in embryonic stem (ES) cells. Such techniquesare well known in the art and are useful for the generation of animalmodels of human disease. (See, e.g., U.S. Pat. No. 5,175,383 and U.S.Pat. No. 5,767,337.) For example, mouse ES cells, such as the mouse129/SvJ cell line, are derived from the early mouse embryo and grown inculture. The ES cells are transformed with a vector containing the geneof interest disrupted by a marker gene, e.g., the neomycinphosphotransferase gene (neo; Capecchi, M. R. (1989) Science244:1288-1292). The vector integrates into the corresponding region ofthe host genome by homologous recombination. Alternatively, homologousrecombination takes place using the Cre-loxP system to knockout a geneof interest in a tissue- or developmental stage-specific manner (Marth,J. D. (1996) Clin. Invest. 97:1999-2002; Wagner, K. U. et al. (1997)Nucleic Acids Res. 25:4323-4330). Transformed ES cells are identifiedand microinjected into mouse cell blastocysts such as those from theC57BL/6 mouse strain. The blastocysts are surgically transferred topseudopregnant dams, and the resulting chimeric progeny are genotypedand bred to produce heterozygous or homozygous strains. Transgenicanimals thus generated may be tested with potential therapeutic or toxicagents.

[0201] Polynucleotides encoding TRICH may also be manipulated in vitroin ES cells derived from human blastocysts. Human ES cells have thepotential to differentiate into at least eight separate cell lineagesincluding endoderm, mesoderm, and ectodermal cell types. These celllineages differentiate into, for example, neural cells, hematopoieticlineages, and cardiomyocytes (Thomson, J. A. et al. (1998) Science282:1145-1147).

[0202] Polynucleotides encoding TRICH can also be used to create“knockin” humanized animals (pigs) or transgenic animals (mice or rats)to model human disease. With knockin technology, a region of apolynucleotide encoding TRICH is injected into animal ES cells, and theinjected sequence integrates into the animal cell genome. Transformedcells are injected into blastulae, and the blastulae are implanted asdescribed above. Transgenic progeny or inbred lines are studied andtreated with potential pharmaceutical agents to obtain information ontreatment of a human disease. Alternatively, a mammal inbred tooverexpress TRICH, e.g., by secreting TRICH in its milk, may also serveas a convenient source of that protein (Janne, J. et al. (1998)Biotechnol. Annu. Rev. 4:55-74).

[0203] Therapeutics

[0204] Chemical and structural similarity, e.g., in the context ofsequences and motifs, exists between regions of TRICH and transportersand ion channels. In addition, the expression of TRICH is closelyassociated with normal tissues such as liver, ileum, skin, brain, dorsalroot ganglion, breast, kidney, lung, pancreas, small intestine, seminalvesicle and placental tissues; normal cells such as promonocytes andbone marrow cells; and tumor tissues such as prostate, frontal lobe,pancreatic, ileal, colon and spleen tumor tissues. Therefore, TRICHappears to play a role in transport, neurological, muscle,immunological, and cell proliferative disorders. In the treatment ofdisorders associated with increased TRICH expression or activity, it isdesirable to decrease the expression or activity of TRICH. In thetreatment of disorders associated with decreased TRICH expression oractivity, it is desirable to increase the expression or activity ofTRICH.

[0205] Therefore, in one embodiment, TRICH or a fragment or derivativethereof may be administered to a subject to treat or prevent a disorderassociated with decreased expression or activity of TRICH. Examples ofsuch disorders include, but are not limited to, a transport disordersuch as akinesia, amyotrophic lateral sclerosis, ataxia telangiectasia,cystic fibrosis, Becker's muscular dystrophy, Bell's palsy,Charcot-Marie Tooth disease, diabetes mellitus, diabetes insipidus,diabetic neuropathy, Duchenne muscular dystrophy, hyperkalemic periodicparalysis, normokalemic periodic paralysis, Parkinson's disease,malignant hyperthermia, multidrug resistance, myasthenia gravis,myotonic dystrophy, catatonia, tardive dyskinesia, dystonias, peripheralneuropathy, cerebral neoplasms, prostate cancer, cardiac disordersassociated with transport, e.g., angina, bradyarrythmia, tachyarrythmia,hypertension, Long QT syndrome, myocarditis, cardiomyopathy, nemalinemyopathy, centronuclear myopathy, lipid myopathy, mitochondrialmyopathy, thyrotoxic myopathy, ethanol myopathy, dermatomyositis,inclusion body myositis, infectious myositis, polymyositis, neurologicaldisorders associated with transport, e.g., Alzheimer's disease, amnesia,bipolar disorder, dementia, depression, epilepsy, Tourette's disorder,paranoid psychoses, and schizophrenia, and other disorders associatedwith transport, e.g., neurofibromatosis, postherpetic neuralgia,trigeminal neuropathy, sarcoidosis, sickle cell anemia, Wilson'sdisease, cataracts, infertility, pulmonary artery stenosis,sensorineural autosomal deafness, hyperglycemia, hypoglycemia, Grave'sdisease, goiter, Cushing's disease, Addison's disease, glucose-galactosemalabsorption syndrome, hypercholesterolemia, adrenoleukodystrophy,Zellweger syndrome, Menkes disease, occipital horn syndrome, von Gierkedisease, cystinuria, iminoglycinuria, Hartup disease, and Fanconidisease; a neurological disorder such as epilepsy, ischemiccerebrovascular disease, stroke, cerebral neoplasms, Alzheimer'sdisease, Pick's disease, Huntington's disease, dementia, Parkinson'sdisease and other extrapyramidal disorders, amyotrophic lateralsclerosis and other motor neuron disorders, progressive neural muscularatrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosisand other demyelinating diseases, bacterial and viral meningitis, brainabscess, subdural empyema, epidural abscess, suppurative intracranialthrombophlebitis, myelitis and radiculitis, viral central nervous systemdisease, prion diseases including kurt, Creutzfeldt-Jakob disease, andGerstmann-Straussler-Scheinker syndrome, fatal familial insomnia,nutritional and metabolic diseases of the nervous system,neurofibromatosis, tuberous sclerosis, cerebelloretinalhemangioblastomatosis, encephalotrigeminal syndrome, mental retardationand other developmental disorders of the central nervous systemincluding Down syndrome, cerebral palsy, neuroskeletal disorders,autonomic nervous system disorders, cranial nerve disorders, spinal corddiseases, muscular dystrophy and other neuromuscular disorders,peripheral nervous system disorders, dermatomyositis and polymyositis,inherited, metabolic, endocrine, and toxic myopathies, myastheniagravis, periodic paralysis, mental disorders including mood, anxiety,and schizophrenic disorders, seasonal affective disorder (SAD),akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia,dystonias, paranoid psychoses, postherpetic neuralgia, Tourette'sdisorder, progressive supranuclear palsy, corticobasal degeneration, andfamilial frontotemporal dementia; a muscle disorder such ascardiomyopathy, myocarditis, Duchenne's muscular dystrophy, Becker'smuscular dystrophy, myotonic dystrophy, central core disease, nemalinemyopathy, centronuclear myopathy, lipid myopathy, mitochondrialmyopathy, infectious myositis, polymyositis, dermatomyositis, inclusionbody myositis, thyrotoxic myopathy, ethanol myopathy, angina,anaphylactic shock, arrhythmias, asthma, cardiovascular shock, Cushing'ssyndrome, hypertension, hypoglycemia, myocardial infarction, migraine,pheochromocytoma, and myopathies including encephalopathy, epilepsy,Kearns-Sayre syndrome, lactic acidosis, myoclonic disorder,ophthalmoplegia, and acid maltase deficiency (AMD, also known as Pompe'sdisease); an immunological disorder such as acquired immunodeficiencysyndrome (AIDS), Addison's disease, adult respiratory distress syndrome,allergies, ankylosing spondylitis, amyloidosis, anemia, asthma,atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis,autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED),bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopicdermatitis, dermatomyositis, diabetes mellitus, emphysema, episodiclymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythemanodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome,gout, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia,irritable bowel syndrome, multiple sclerosis, myasthenia gravis,myocardial or pericardial inflammation, osteoarthritis, osteoporosis,pancreatitis, polymyositis, psoriasis, Reiter's syndrome, rheumatoidarthritis, scleroderma, Sjögren's syndrome, systemic anaphylaxis,systemic lupus erythematosus, systemic sclerosis, thrombocytopenicpurpura, ulcerative colitis, uveitis, Werner syndrome, complications ofcancer, hemodialysis, and extracorporeal circulation, viral, bacterial,fungal, parasitic, protozoal and helminthic infections, and trauma; anda cell proliferative disorder such as actinic keratosis,arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixedconnective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnalhemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia,and cancers including adenocarcinoma, leukemia, lymphoma, melanoma,myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of theadrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gallbladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung,muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands,skin, spleen, testis, thymus, thyroid, and uterus.

[0206] In another embodiment, a vector capable of expressing TRICH or afragment or derivative thereof may be administered to a subject to treator prevent a disorder associated with decreased expression or activityof TRICH including, but not limited to, those described above.

[0207] In a further embodiment, a composition comprising a substantiallypurified TRICH in conjunction with a suitable pharmaceutical carrier maybe administered to a subject to treat or prevent a disorder associatedwith decreased expression or activity of TRICH including, but notlimited to, those provided above.

[0208] In still another embodiment, an agonist which modulates theactivity of TRICH may be administered to a subject to treat or prevent adisorder associated with decreased expression or activity of TRICHincluding, but not limited to, those listed above.

[0209] In a further embodiment, an antagonist of TRICH may beadministered to a subject to treat or prevent a disorder associated withincreased expression or activity of TRICH. Examples of such disordersinclude, but are not limited to, those transport, neurological, muscle,immunological, and cell proliferative disorders described above. In oneaspect, an antibody which specifically binds TRICH may be used directlyas an antagonist or indirectly as a targeting or delivery mechanism forbringing a pharmaceutical agent to cells or tissues which express TRICH.

[0210] In an additional embodiment, a vector expressing the complementof the polynucleotide encoding TRICH may be administered to a subject totreat or prevent a disorder associated with increased expression oractivity of TRICH including, but not limited to, those described above.

[0211] In other embodiments, any of the proteins, antagonists,antibodies, agonists, complementary sequences, or vectors of theinvention may be administered in combination with other appropriatetherapeutic agents. Selection of the appropriate agents for use incombination therapy may be made by one of ordinary skill in the art,according to conventional pharmaceutical principles. The combination oftherapeutic agents may act synergistically to effect the treatment orprevention of the various disorders described above. Using thisapproach, one may be able to achieve therapeutic efficacy with lowerdosages of each agent, thus reducing the potential for adverse sideeffects.

[0212] An antagonist of TRICH may be produced using methods which aregenerally known in the art. In particular, purified TRICH may be used toproduce antibodies or to screen libraries of pharmaceutical agents toidentify those which specifically bind TRICH. Antibodies to TRICH mayalso be generated using methods that are well known in the art. Suchantibodies may include, but are not limited to, polyclonal, monoclonal,chimeric, and single chain antibodies, Fab fragments, and fragmentsproduced by a Fab expression library. Neutralizing antibodies (i.e.,those which inhibit dimer formation) are generally preferred fortherapeutic use.

[0213] For the production of antibodies, various hosts including goats,rabbits, rats, mice, humans, and others may be immunized by injectionwith TRICH or with any fragment or oligopeptide thereof which hasimmunogenic properties. Depending on the host species, various adjuvantsmay be used to increase immunological response. Such adjuvants include,but are not limited to, Freund's, mineral gels such as aluminumhydroxide, and surface active substances such as lysolecithin, pluronicpolyols, polyanions, peptides, oil emulsions, KLH, and dinitrophenol.Among adjuvants used in humans, BCG (bacilli Calmette-Guerin) andCorynebacterium parvum are especially preferable.

[0214] It is preferred that the oligopeptides, peptides, or fragmentsused to induce antibodies to TRICH have an amino acid sequenceconsisting of at least about 5 amino acids, and generally will consistof at least about 10 amino acids. It is also preferable that theseoligopeptides, peptides, or fragments are identical to a portion of theamino acid sequence of the natural protein. Short stretches of TRICHamino acids may be fused with those of another protein, such as KLH, andantibodies to the chimeric molecule may be produced.

[0215] Monoclonal antibodies to TRICH may be prepared using anytechnique which provides for the production of antibody molecules bycontinuous cell lines in culture. These include, but are not limited to,the hybridoma technique, the human B-cell hybridoma technique, and theEBV-hybridoma technique. (See, e.g., Kohler, G. et al. (1975) Nature256:495-497; Kozbor, D. et al. (1985) J. Immunol. Methods 81:31-42;Cote, R. J. et al. (1983) Proc. Natl. Acad. Sci. USA 80:2026-2030; andCole, S. P. et al. (1984) Mol. Cell Biol. 62:109-120.)

[0216] In addition, techniques developed for the production of “chimericantibodies,” such as the splicing of mouse antibody genes to humanantibody genes to obtain a molecule with appropriate antigen specificityand biological activity, can be used. (See, e.g., Morrison, S. L. et al.(1984) Proc. Natl. Acad. Sci. USA 81:6851-6855; Neuberger, M. S. et al.(1984) Nature 312:604-608; and Takeda, S. et al. (1985) Nature314:452-454.) Alternatively, techniques described for the production ofsingle chain antibodies may be adapted, using methods known in the art,to produce TRICH-specific single chain antibodies. Antibodies withrelated specificity, but of distinct idiotypic composition, may begenerated by chain shuffling from random combinatorial immunoglobulinlibraries. (See, e.g., Burton, D. R. (1991) Proc. Natl. Acad. Sci. USA88:10134-10137.)

[0217] Antibodies may also be produced by inducing in vivo production inthe lymphocyte population or by screening immunoglobulin libraries orpanels of highly specific binding reagents as disclosed in theliterature. (See, e.g., Orlandi, R. et al. (1989) Proc. Natl. Acad. Sci.USA 86:3833-3837; Winter, G. et al. (1991) Nature 349:293-299.)

[0218] Antibody fragments which contain specific binding sites for TRICHmay also be generated. For example, such fragments include, but are notlimited to, F(ab′)₂ fragments produced by pepsin digestion of theantibody molecule and Fab fragments generated by reducing the disulfidebridges of the F(ab′)2 fragments. Alternatively, Fab expressionlibraries may be constructed to allow rapid and easy identification ofmonoclonal Fab fragments with the desired specificity. (See, e.g., Huse,W. D. et al. (1989) Science 246:1275-1281.)

[0219] Various immunoassays may be used for screening to identifyantibodies having the desired specificity. Numerous protocols forcompetitive binding or immunoradiometric assays using either polyclonalor monoclonal antibodies with established specificities are well knownin the art. Such immunoassays typically involve the measurement ofcomplex formation between TRICH and its specific antibody. A two-site,monoclonal-based immunoassay utilizing monoclonal antibodies reactive totwo non-interfering TRICH epitopes is generally used, but a competitivebinding assay may also be employed (Pound, supra).

[0220] Various methods such as Scatchard analysis in conjunction withradioimmunoassay techniques may be used to assess the affinity ofantibodies for TRICH. Affinity is expressed as an association constant,K_(a), which is defined as the molar concentration of TRICH-antibodycomplex divided by the molar concentrations of free antigen and freeantibody under equilibrium conditions. The K_(a) determined for apreparation of polyclonal antibodies, which are heterogeneous in theiraffinities for multiple TRICH epitopes, represents the average affinity,or avidity, of the antibodies for TRICH. The K_(a) determined for apreparation of monoclonal antibodies, which are monospecific for aparticular TRICH epitope, represents a true measure of affinity.High-affinity antibody preparations with K_(a) ranging from about 10⁹ to10¹² L/mole are preferred for use in immunoassays in which theTRICH-antibody complex must withstand rigorous manipulations.Low-affinity antibody preparations with K_(a) ranging from about 10⁶ to10⁷ L/mole are preferred for use in immunopurification and similarprocedures which ultimately require dissociation of TRICH, preferably inactive form, from the antibody (Catty, D. (1988) Antibodies. Volume I: APractical Approach, IRL Press, Washington D.C.; Liddell, J. E. and A.Cryer (1991) A Practical Guide to Monoclonal Antibodies, John Wiley &Sons, New York N.Y.).

[0221] The titer and avidity of polyclonal antibody preparations may befurther evaluated to determine the quality and suitability of suchpreparations for certain downstream applications. For example, apolyclonal antibody preparation containing at least 1-2 mg specificantibody/ml, preferably 5-10 mg specific antibody/ml, is generallyemployed in procedures requiring precipitation of TRICH-antibodycomplexes. Procedures for evaluating antibody specificity, titer, andavidity, and guidelines for antibody quality and usage in variousapplications, are generally available. (See, e.g., Catty, supra, andColigan et al. supra.)

[0222] In another embodiment of the invention, the polynucleotidesencoding TRICH, or any fragment or complement thereof, may be used fortherapeutic purposes. In one aspect, modifications of gene expressioncan be achieved by designing complementary sequences or antisensemolecules (DNA, RNA, PNA, or modified oligonucleotides) to the coding orregulatory regions of the gene encoding TRICH. Such technology is wellknown in the art, and antisense oligonucleotides or larger fragments canbe designed from various locations along the coding or control regionsof sequences encoding TRICH. (See, e.g., Agrawal, S., ed. (1996)Antisense Therapeutics, Humana Press Inc., Totawa N.J.)

[0223] In therapeutic use, any gene delivery system suitable forintroduction of the antisense sequences into appropriate target cellscan be used. Antisense sequences can be delivered intracellularly in theform of an expression plasmid which, upon transcription, produces asequence complementary to at least a portion of the cellular sequenceencoding the target protein. (See, e.g., Slater, J. E. et al. (1998) J.Allergy Cli. Immunol. 102(3):469-475; and Scanlon, K. J. et al. (1995)9(13):1288-1296.) Antisense sequences can also be introducedintracellularly through the use of viral vectors, such as retrovirus andadeno-associated virus vectors. (See, e.g., Miller, A. D. (1990) Blood76:271; Ausubel, supra; Uckert, W. and W. Walther (1994) Pharmacol.Ther. 63(3):323-347.) Other gene delivery mechanisms includeliposome-derived systems, artificial viral envelopes, and other systemsknown in the art. (See, e.g., Rossi, J. J. (1995) Br. Med. Bull.51(1):217-225; Boado, R. J. et al. (1998) J. Pharm. Sci.87(11):1308-1315; and Morris, M. C. et al. (1997) Nucleic Acids Res.25(14):2730-2736.)

[0224] In another embodiment of the invention, polynucleotides encodingTRICH may be used for somatic or germline gene therapy. Gene therapy maybe performed to (i) correct a genetic deficiency (e.g., in the cases ofsevere combined immunodeficiency (SCID)-X1 disease characterized byX-linked inheritance (Cavazzana-Calvo, M. et al. (2000) Science288:669-672), severe combined immunodeficiency syndrome associated withan inherited adenosine deaminase (ADA) deficiency (Blaese, R. M. et al.(1995) Science 270:475-480; Bordignon, C. et al. (1995) Science270:470-475), cystic fibrosis (Zabner, J. et al. (1993) Cell 75:207-216;Crystal, R. G. et al. (1995) Hum. Gene Therapy 6:643-666; Crystal, R. G.et al. (1995) Hum. Gene Therapy 6:667-703), thalassamias, familialhypercholesterolemia, and hemophilia resulting from Factor VIII orFactor IX deficiencies (Crystal, R. G. (1995) Science 270:404-410;Verma, I. M. and N. Somia (1997) Nature 389:239-242)), (ii) express aconditionally lethal gene product (e.g., in the case of cancers whichresult from unregulated cell proliferation), or (iii) express a proteinwhich affords protection against intracellular parasites (e.g., againsthuman retroviruses, such as human immunodeficiency virus (HIV)(Baltimore, D. (1988) Nature 335:395-396; Poeschla, E. et al. (1996)Proc. Natl. Acad. Sci. USA. 93:11395-11399), hepatitis B or C virus(HBV, HCV); fungal parasites, such as Candida albicans andParacoccidioides brasiliensis; and protozoan parasites such asPlasmodium falciparum and Trypanosoma cruzi). In the case where agenetic deficiency in TRICH expression or regulation causes disease, theexpression of TRICH from an appropriate population of transduced cellsmay alleviate the clinical manifestations caused by the geneticdeficiency.

[0225] In a further embodiment of the invention, diseases or disorderscaused by deficiencies in TRICH are treated by constructing mammalianexpression vectors encoding TRICH and introducing these vectors bymechanical means into TRICH-deficient cells. Mechanical transfertechnologies for use with cells in vivo or ex vitro include (i) directDNA microinjection into individual cells, (ii) ballistic gold particledelivery, (iii) liposome-mediated transfection, (iv) receptor-mediatedgene transfer, and (v) the use of DNA transposons (Morgan, R. A. and W.F. Anderson (1993) Annu. Rev. Biochem. 62:191-217; Ivics, Z. (1997) Cell91:501-510; Boulay, J -L. and H. Récipon (1998) Curr. Opin. Biotechnol.9:445-450).

[0226] Expression vectors that may be effective for the expression ofTRICH include, but are not limited to, the PCDNA 3.1, EPITAG, PRCCMV2,PREP, PVAX vectors (Invitrogen, Carlsbad Calif.), PCMV-SCRIPT, PCMV-TAG,PEGSH/PERV (Stratagene, La Jolla Calif.), and PTET-OFF, PTET-ON, PTRE2,PTRE2-LUC, PTK-HYG (Clontech, Palo Alto Calif.). TRICH may be expressedusing (i) a constitutively active promoter, (e.g., from cytomegalovirus(CMV), Rous sarcoma virus (RSV), SV40 virus, thymidine kinase (TK), orβ-actin genes), (ii) an inducible promoter (e.g., thetetracycline-regulated promoter (Gossen, M. and H. Bujard (1992) Proc.Natl. Acad. Sci. USA 89:5547-5551; Gossen, M. et al. (1995) Science268:1766-1769; Rossi, F. M. V. and H. M. Blau (1998) Curr. Opin.Biotechnol. 9:451-456), commercially available in the T-REX plasmid(Invitrogen)); the ecdysone-inducible promoter (available in theplasmids PVGRXR and PIND; Invitrogen); the FK506/rapamycin induciblepromoter; or the RU486/mifepristone inducible promoter (Rossi, F. M. V.and Blau, H. M. supra)), or (iii) a tissue-specific promoter or thenative promoter of the endogenous gene encoding TRICH from a normalindividual.

[0227] Commercially available liposome transformation kits (e.g., thePERFECT LIPID TRANSFECTION KIT, available from Invitrogen) allow onewith ordinary skill in the art to deliver polynucleotides to targetcells in culture and require minimal effort to optimize experimentalparameters. In the alternative, transformation is performed using thecalcium phosphate method (Graham, F. L. and A. J. Eb (1973) Virology52:456-467), or by electroporation (Neumann, E. et al. (1982) EMBO J.1:841-845). The introduction of DNA to primary cells requiresmodification of these standardized mammalian transfection protocols.

[0228] In another embodiment of the invention, diseases or disorderscaused by genetic defects with respect to TRICH expression are treatedby constructing a retrovirus vector consisting of (i) the polynucleotideencoding TRICH under the control of an independent promoter or theretrovirus long terminal repeat (LTR) promoter, (ii) appropriate RNApackaging signals, and (iii) a Rev-responsive element (RRE) along withadditional retrovirus cis-acting RNA sequences and coding sequencesrequired for efficient vector propagation. Retrovirus vectors (e.g., PFBand PFBNEO) are commercially available (Stratagene) and are based onpublished data (Riviere, I. et al. (1995) Proc. Natl. Acad. Sci. USA92:6733-6737), incorporated by reference herein. The vector ispropagated in an appropriate vector producing cell line (VPCL) thatexpresses an envelope gene with a tropism for receptors on the targetcells or a promiscuous envelope protein such as VSVg (Armentano, D. etal. (1987) J. Virol. 61:1647-1650; Bender, M. A. et al. (1987) J. Virol.61:1639-1646; Adam, M. A. and A. D. Miller (1988) J. Virol.62:3802-3806; Dull, T. et al. (1998) J. Virol. 72:8463-8471; Zufferey,R. et al. (1998) J. Virol. 72:9873-9880). U.S. Pat. No. 5,910,434 toRigg (“Method for obtaining retrovirus packaging cell lines producinghigh transducing efficiency retroviral supernatant”) discloses a methodfor obtaining retrovirus packaging cell lines and is hereby incorporatedby reference. Propagation of retrovirus vectors, transduction of apopulation of cells (e.g., CD⁴⁺ T-cells), and the return of transducedcells to a patient are procedures well known to persons skilled in theart of gene therapy and have been well documented (Ranga, U. et al.(1997) J. Virol. 71:7020-7029; Bauer, G. et al. (1997) Blood89:2259-2267; Bonyhadi, M. L. (1997) J. Virol. 71:4707-4716; Ranga, U.et al. (1998) Proc. Natl. Acad. Sci. USA 95:1201-1206; Su, L. (1997)Blood 89:2283-2290).

[0229] In the alternative, an adenovirus-based gene therapy deliverysystem is used to deliver polynucleotides encoding TRICH to cells whichhave one or more genetic abnormalities with respect to the expression ofTRICH. The construction and packaging of adenovirus-based vectors arewell known to those with ordinary skill in the art. Replicationdefective adenovirus vectors have proven to be versatile for importinggenes encoding immunoregulatory proteins into intact islets in thepancreas (Csete, M. E. et al. (1995) Transplantation 27:263-268).Potentially useful adenoviral vectors are described in U.S. Pat. No.5,707,618 to Armentano (“Adenovirus vectors for gene therapy”), herebyincorporated by reference. For adenoviral vectors, see also Antinozzi,P. A. et al. (1999) Annu. Rev. Nutr. 19:511-544 and Verma, I. M. and N.Somia (1997) Nature 18:389:239-242, both incorporated by referenceherein.

[0230] In another alternative, a herpes-based, gene therapy deliverysystem is used to deliver polynucleotides encoding TRICH to target cellswhich have one or more genetic abnormalities with respect to theexpression of TRICH. The use of herpes simplex virus (HSV)-based vectorsmay be especially valuable for introducing TRICH to cells of the centralnervous system, for which HSV has a tropism. The construction andpackaging of herpes-based vectors are well known to those with ordinaryskill in the art. A replication-competent herpes simplex virus (HSV)type 1-based vector has been used to deliver a reporter gene to the eyesof primates (Liu, X. et al. (1999) Exp. Eye Res. 169:385-395). Theconstruction of a HSV-1 virus vector has also been disclosed in detailin U.S. Pat. No. 5,804,413 to DeLuca (“Herpes simplex virus strains forgene transfer”), which is hereby incorporated by reference. U.S. Pat.No. 5,804,413 teaches the use of recombinant HSV d92 which consists of agenome containing at least one exogenous gene to be transferred to acell under the control of the appropriate promoter for purposesincluding human gene therapy. Also taught by this patent are theconstruction and use of recombinant HSV strains deleted for ICP4, ICP27and ICP22. For HSV vectors, see also Goins, W. F. et al. (1999) J.Virol. 73:519-532 and Xu, H. et al. (1994) Dev. Biol. 163:152-161,hereby incorporated by reference. The manipulation of cloned herpesvirussequences, the generation of recombinant virus following thetransfection of multiple plasmids containing different segments of thelarge herpesvirus genomes, the growth and propagation of herpesvirus,and the infection of cells with herpesvirus are techniques well known tothose of ordinary skill in the art.

[0231] In another alternative, an alphavirus (positive, single-strandedRNA virus) vector is used to deliver polynucleotides encoding TRICH totarget cells. The biology of the prototypic alphavirus, Semliki ForestVirus (SFV), has been studied extensively and gene transfer vectors havebeen based on the SFV genome (Garoff, H. and K. -J. Li (1998) Curr.Opin. Biotechnol. 9:464-469). During alphavirus RNA replication, asubgenomic RNA is generated that normally encodes the viral capsidproteins. This subgenomic RNA replicates to higher levels than the fulllength genomic RNA, resulting in the overproduction of capsid proteinsrelative to the viral proteins with enzymatic activity (e.g., proteaseand polymerase). Similarly, inserting the coding sequence for TRICH intothe alphavirus genome in place of the capsid-coding region results inthe production of a large number of TRICH-coding RNAs and the synthesisof high levels of TRICH in vector transduced cells. While alphavirusinfection is typically associated with cell lysis within a few days, theability to establish a persistent infection in hamster normal kidneycells (BHK-21) with a variant of Sindbis virus (SIN) indicates that thelytic replication of alphaviruses can be altered to suit the needs ofthe gene therapy application (Dryga, S. A. et al. (1997) Virology228:74-83). The wide host range of alphaviruses will allow theintroduction of TRICH into a variety of cell types. The specifictransduction of a subset of cells in a population may require thesorting of cells prior to transduction. The methods of manipulatinginfectious cDNA clones of alphaviruses, performing alphavirus cDNA andRNA transfections, and performing alphavirus infections, are well knownto those with ordinary skill in the art.

[0232] Oligonucleotides derived from the transcription initiation site,e.g., between about positions −10 and +10 from the start site, may alsobe employed to inhibit gene expression. Similarly, inhibition can beachieved using triple helix base-pairing methodology. Triple helixpairing is useful because it causes inhibition of the ability of thedouble helix to open sufficiently for the binding of polymerases,transcription factors, or regulatory molecules. Recent therapeuticadvances using triplex DNA have been described in the literature. (See,e.g., Gee, J. E. et al. (1994) in Huber, B. E. and B. I. Carr, Molecularand Immunologic Approaches, Futura Publishing, Mt. Kisco N.Y., pp.163-177.) A complementary sequence or antisense molecule may also bedesigned to block translation of mRNA by preventing the transcript frombinding to ribosomes.

[0233] Ribozymes, enzymatic RNA molecules, may also be used to catalyzethe specific cleavage of RNA. The mechanism of ribozyme action involvessequence-specific hybridization of the ribozyme molecule tocomplementary target RNA, followed by endonucleolytic cleavage. Forexample, engineered hammerhead motif ribozyme molecules may specificallyand efficiently catalyze endonucleolytic cleavage of sequences encodingTRICH.

[0234] Specific ribozyme cleavage sites within any potential RNA targetare initially identified by scanning the target molecule for ribozymecleavage sites, including the following sequences: GUA, GUU, and GUC.Once identified, short RNA sequences of between 15 and 20ribonucleotides, corresponding to the region of the target genecontaining the cleavage site, may be evaluated for secondary structuralfeatures which may render the oligonucleotide inoperable. Thesuitability of candidate targets may also be evaluated by testingaccessibility to hybridization with complementary oligonucleotides usingribonuclease protection assays.

[0235] Complementary ribonucleic acid molecules and ribozymes of theinvention may be prepared by any method known in the art for thesynthesis of nucleic acid molecules. These include techniques forchemically synthesizing oligonucleotides such as solid phasephosphoramidite chemical synthesis. Alternatively, RNA molecules may begenerated by in vitro and in vivo transcription of DNA sequencesencoding TRICH. Such DNA sequences may be incorporated into a widevariety of vectors with suitable RNA polymerase promoters such as T7 orSP6. Alternatively, these cDNA constructs that synthesize complementaryRNA, constitutively or inducibly, can be introduced into cell lines,cells, or tissues.

[0236] RNA molecules may be modified to increase intracellular stabilityand half-life. Possible modifications include, but are not limited to,the addition of flanking sequences at the 5′ and/or 3′ ends of themolecule, or the use of phosphorothioate or 2′ O-methyl rather thanphosphodiesterase linkages within the backbone of the molecule. Thisconcept is inherent in the production of PNAs and can be extended in allof these molecules by the inclusion of nontraditional bases such asinosine, queosine, and wybutosine, as well as acetyl-, methyl-, thio-,and similarly modified forms of adenine, cytidine, guanine, thymine, anduridine which are not as easily recognized by endogenous endonucleases.

[0237] An additional embodiment of the invention encompasses a methodfor screening for a compound which is effective in altering expressionof a polynucleotide encoding TRICH. Compounds which may be effective inaltering expression of a specific polynucleotide may include, but arenot limited to, oligonucleotides, antisense oligonucleotides, triplehelix-forming oligonucleotides, transcription factors and otherpolypeptide transcriptional regulators, and non-macromolecular chemicalentities which are capable of interacting with specific polynucleotidesequences. Effective compounds may alter polynucleotide expression byacting as either inhibitors or promoters of polynucleotide expression.Thus, in the treatment of disorders associated with increased TRICHexpression or activity, a compound which specifically inhibitsexpression of the polynucleotide encoding TRICH may be therapeuticallyuseful, and in the treatment of disorders associated with decreasedTRICH expression or activity, a compound which specifically promotesexpression of the polynucleotide encoding TRICH may be therapeuticallyuseful.

[0238] At least one, and up to a plurality, of test compounds may bescreened for effectiveness in altering expression of a specificpolynucleotide. A test compound may be obtained by any method commonlyknown in the art, including chemical modification of a compound known tobe effective in altering polynucleotide expression; selection from anexisting, commercially-available or proprietary library ofnaturally-occurring or non-natural chemical compounds; rational designof a compound based on chemical and/or structural properties of thetarget polynucleotide; and selection from a library of chemicalcompounds created combinatorially or randomly. A sample comprising apolynucleotide encoding TRICH is exposed to at least one test compoundthus obtained. The sample may comprise, for example, an intact orpermeabilized cell, or an in vitro cell-free or reconstitutedbiochemical system. Alterations in the expression of a polynucleotideencoding TRICH are assayed by any method commonly known in the art.Typically, the expression of a specific nucleotide is detected byhybridization with a probe having a nucleotide sequence complementary tothe sequence of the polynucleotide encoding TRICH. The amount ofhybridization may be quantified, thus forming the basis for a comparisonof the expression of the polynucleotide both with and without exposureto one or more test compounds. Detection of a change in the expressionof a polynucleotide exposed to a test compound indicates that the testcompound is effective in altering the expression of the polynucleotide.A screen for a compound effective in altering expression of a specificpolynucleotide can be carried out, for example, using aSchizosaccharomyces pombe gene expression system (Atkins, D. et al.(1999) U.S. Pat. No. 5,932,435; Arndt, G. M. et al. (2000) Nucleic AcidsRes. 28:E15) or a human cell line such as HeLa cell (Clarke, M. L. etal. (2000) Biochem. Biophys. Res. Commun. 268:8-13). A particularembodiment of the present invention involves screening a combinatoriallibrary of oligonucleotides (such as deoxyribonucleotides,ribonucleotides, peptide nucleic acids, and modified oligonucleotides)for antisense activity against a specific polynucleotide sequence(Bruice, T. W. et al. (1997) U.S. Pat. No. 5,686,242; Bruice, T. W. etal. (2000) U.S. Pat. No. 6,022,691).

[0239] Many methods for introducing vectors into cells or tissues areavailable and equally suitable for use in vivo, in vitro, and ex vivo.For ex vivo therapy, vectors may be introduced into stem cells takenfrom the patient and clonally propagated for autologous transplant backinto that same patient. Delivery by transfection, by liposomeinjections, or by polycationic amino polymers may be achieved usingmethods which are well known in the art. (See, e.g., Goldman, C. K. etal. (1997) Nat. Biotechnol. 15:462-466.)

[0240] Any of the therapeutic methods described above may be applied toany subject in need of such therapy, including, for example, mammalssuch as humans, dogs, cats, cows, horses, rabbits, and monkeys.

[0241] An additional embodiment of the invention relates to theadministration of a composition which generally comprises an activeingredient formulated with a pharmaceutically acceptable excipient.Excipients may include, for example, sugars, starches, celluloses, gums,and proteins. Various formulations are commonly known and are thoroughlydiscussed in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing, Easton Pa.). Such compositions may consist of TRICH,antibodies to TRICH, and mimetics, agonists, antagonists, or inhibitorsof TRICH.

[0242] The compositions utilized in this invention may be administeredby any number of routes including, but not limited to, oral,intravenous, intramuscular, intra-arterial, intramedullary, intrathecal,intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal,intranasal, enteral, topical, sublingual, or rectal means.

[0243] Compositions for pulmonary administration may be prepared inliquid or dry powder form. These compositions are generally aerosolizedimmediately prior to inhalation by the patient. In the case of smallmolecules (e.g. traditional low molecular weight organic drugs), aerosoldelivery of fast-acting formulations is well-known in the art. In thecase of macromolecules (e.g. larger peptides and proteins), recentdevelopments in the field of pulmonary delivery via the alveolar regionof the lung have enabled the practical delivery of drugs such as insulinto blood circulation (see, e.g., Patton, J. S. et al., U.S. Pat. No.5,997,848). Pulmonary delivery has the advantage of administrationwithout needle injection, and obviates the need for potentially toxicpenetration enhancers.

[0244] Compositions suitable for use in the invention includecompositions wherein the active ingredients are contained in aneffective amount to achieve the intended purpose. The determination ofan effective dose is well within the capability of those skilled in theart.

[0245] Specialized forms of compositions may be prepared for directintracellular delivery of macromolecules comprising TRICH or fragmentsthereof. For example, liposome preparations containing acell-impermeable macromolecule may promote cell fusion and intracellulardelivery of the macromolecule. Alternatively, TRICH or a fragmentthereof may be joined to a short cationic N-terminal portion from theHIV Tat-1 protein. Fusion proteins thus generated have been found totransduce into the cells of all tissues, including the brain, in a mousemodel system (Schwarze, S. R. et al. (1999) Science 285:1569-1572).

[0246] For any compound, the therapeutically effective dose can beestimated initially either in cell culture assays, e.g., of neoplasticcells, or in animal models such as mice, rats, rabbits, dogs, monkeys,or pigs. An animal model may also be used to determine the appropriateconcentration range and route of administration. Such information canthen be used to determine useful doses and routes for administration inhumans.

[0247] A therapeutically effective dose refers to that amount of activeingredient, for example TRICH or fragments thereof, antibodies of TRICH,and agonists, antagonists or inhibitors of TRICH, which ameliorates thesymptoms or condition. Therapeutic efficacy and toxicity may bedetermined by standard pharmaceutical procedures in cell cultures orwith experimental animals, such as by calculating the ED₅₀ (the dosetherapeutically effective in 50% of the population) or LD₅₀ (the doselethal to 50% of the population) statistics. The dose ratio of toxic totherapeutic effects is the therapeutic index, which can be expressed asthe LD₅₀/ED₅₀ ratio. Compositions which exhibit large therapeuticindices are preferred. The data obtained from cell culture assays andanimal studies are used to formulate a range of dosage for human use.The dosage contained in such compositions is preferably within a rangeof circulating concentrations that includes the ED₅₀ with little or notoxicity. The dosage varies within this range depending upon the dosageform employed, the sensitivity of the patient, and the route ofadministration.

[0248] The exact dosage will be determined by the practitioner, in lightof factors related to the subject requiring treatment. Dosage andadministration are adjusted to provide sufficient levels of the activemoiety or to maintain the desired effect Factors which may be taken intoaccount include the severity of the disease state, the general health ofthe subject, the age, weight, and gender of the subject, time andfrequency of administration, drug combination(s), reactionsensitivities, and response to therapy. Long-acting compositions may beadministered every 3 to 4 days, every week, or biweekly depending on thehalf-life and clearance rate of the particular formulation.

[0249] Normal dosage amounts may vary from about 0.1 μg to 100,000 μg,up to a total dose of about 1 gram, depending upon the route ofadministration. Guidance as to particular dosages and methods ofdelivery is provided in the literature and generally available topractitioners in the art. Those skilled in the art will employ differentformulations for nucleotides than for proteins or their inhibitors.Similarly, delivery of polynucleotides or polypeptides will be specificto particular cells, conditions, locations, etc.

[0250] Diagnostics

[0251] In another embodiment, antibodies which specifically bind TRICHmay be used for the diagnosis of disorders characterized by expressionof TRICH, or in assays to monitor patients being treated with TRICH oragonists, antagonists, or inhibitors of TRICH. Antibodies useful fordiagnostic purposes may be prepared in the same manner as describedabove for therapeutics. Diagnostic assays for TRICH include methodswhich utilize the antibody and a label to detect TRICH in human bodyfluids or in extracts of cells or tissues. The antibodies may be usedwith or without modification, and may be labeled by covalent ornon-covalent attachment of a reporter molecule. A wide variety ofreporter molecules, several of which are described above, are known inthe art and may be used.

[0252] A variety of protocols for measuring TRICH, including ELISAs,RIAs, and FACS, are known in the art and provide a basis for diagnosingaltered or abnormal levels of TRICH expression. Normal or standardvalues for TRICH expression are established by combining body fluids orcell extracts taken from normal mammalian subjects, for example, humansubjects, with antibodies to TRICH under conditions suitable for complexformation. The amount of standard complex formation may be quantitatedby various methods, such as photometric means. Quantities of TRICHexpressed in subject, control, and disease samples from biopsied tissuesare compared with the standard values. Deviation between standard andsubject values establishes the parameters for diagnosing disease.

[0253] In another embodiment of the invention, the polynucleotidesencoding TRICH may be used for diagnostic purposes. The polynucleotideswhich may be used include oligonucleotide sequences, complementary RNAand DNA molecules, and PNAs. The polynucleotides may be used to detectand quantify gene expression in biopsied tissues in which expression ofTRICH may be correlated with disease. The diagnostic assay may be usedto determine absence, presence, and excess expression of TRICH, and tomonitor regulation of TRICH levels during therapeutic intervention.

[0254] In one aspect, hybridization with PCR probes which are capable ofdetecting polynucleotide sequences, including genomic sequences,encoding TRICH or closely related molecules may be used to identifynucleic acid sequences which encode TRICH. The specificity of the probe,whether it is made from a highly specific region, e.g., the 5′regulatory region, or from a less specific region, e.g., a conservedmotif, and the stringency of the hybridization or amplification willdetermine whether the probe identifies only naturally occurringsequences encoding TRICH, allelic variants, or related sequences.

[0255] Probes may also be used for the detection of related sequences,and may have at least 50% sequence identity to any of the TRICH encodingsequences. The hybridization probes of the subject invention may be DNAor RNA and may be derived from the sequence of SEQ ID NO: 28-54 or fromgenomic sequences including promoters, enhancers, and introns of theTRICH gene.

[0256] Means for producing specific hybridization probes for DNAsencoding TRICH include the cloning of polynucleotide sequences encodingTRICH or TRICH derivatives into vectors for the production of mRNAprobes. Such vectors are known in the art, are commercially available,and may be used to synthesize RNA probes in vitro by means of theaddition of the appropriate RNA polymerases and the appropriatelabeled-nucleotides. Hybridization probes may be labeled by a variety ofreporter groups, for example, by radionuclides such as ³²P or ³⁵S, or byenzymatic labels, such as alkaline phosphatase coupled to the probe viaavidin/biotin coupling systems, and the like.

[0257] Polynucleotide sequences encoding TRICH may be used for thediagnosis of disorders associated with expression of TRICH. Examples ofsuch disorders include, but are not limited to, a transport disordersuch as akinesia, amyotrophic lateral sclerosis, ataxia telangiectasia,cystic fibrosis, Becker's muscular dystrophy, Bell's palsy,Charcot-Marie Tooth disease, diabetes mellitus, diabetes insipidus,diabetic neuropathy, Duchenne muscular dystrophy, hyperkalemic periodicparalysis, normokalemic periodic paralysis, Parkinson's disease,malignant hyperthermia, multidrug resistance, myasthenia gravis,myotonic dystrophy, catatonia, tardive dyskinesia, dystonias, peripheralneuropathy, cerebral neoplasms prostate cancer, cardiac disordersassociated with transport, e.g., angina, bradyarrythmia, tachyarrythmia,hypertension, Long QT syndrome, myocarditis, cardiomyopathy, nemalinemyopathy, centronuclear myopathy, lipid myopathy, mitochondrialmyopathy, thyrotoxic myopathy, ethanol myopathy, dermatomyositis,inclusion body myositis, infectious myositis, polymyositis, neurologicaldisorders associated with transport, e.g., Alzheimer's disease, amnesia,bipolar disorder, dementia, depression, epilepsy, Tourette's disorder,paranoid psychoses, and schizophrenia, and other disorders associatedwith transport, e.g., neurofibromatosis, postherpetic neuralgia,trigeminal neuropathy, sarcoidosis, sickle cell anemia, Wilson'sdisease, cataracts, infertility, pulmonary artery stenosis,sensorineural autosomal deafness, hyperglycemia, hypoglycemia, Grave'sdisease, goiter, Cushing's disease, Addison's disease, glucose-galactosemalabsorption syndrome, hypercholesterolemia, adrenoleukodystrophy,Zellweger syndrome, Menkes disease, occipital horn syndrome, von Gierkedisease, cystinuria, iminoglycinuria, Hartup disease, and Fanconidisease; a neurological disorder such as epilepsy, ischemiccerebrovascular disease, stroke, cerebral neoplasms, Alzheimer'sdisease, Pick's disease, Huntington's disease, dementia, Parkinson'sdisease and other extrapyramidal disorders, amyotrophic lateralsclerosis and other motor neuron disorders, progressive neural muscularatrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosisand other demyelinating diseases, bacterial and viral meningitis, brainabscess, subdural empyema, epidural abscess, suppurative intracranialthrombophlebitis, myelitis and radiculitis, viral central nervous systemdisease, prion diseases including kuru, Creutzfeldt-Jakob disease, andGerstmann-Straussler-Scheinker syndrome, fatal familial insomnia,nutritional and metabolic diseases of the nervous system,neurofibromatosis, tuberous sclerosis, cerebelloretinalhemangioblastomatosis, encephalotrigeminal syndrome, mental retardationand other developmental disorders of the central nervous systemincluding Down syndrome, cerebral palsy, neuroskeletal disorders,autonomic nervous system disorders, cranial nerve disorders, spinal corddiseases, muscular dystrophy and other neuromuscular disorders,peripheral nervous system disorders, dermatomyositis and polymyositis,inherited, metabolic, endocrine, and toxic myopathies, myastheniagravis, periodic paralysis, mental disorders including mood, anxiety,and schizophrenic disorders, seasonal affective disorder (SAD),akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia,dystonias, paranoid psychoses, postherpetic neuralgia, Tourette'sdisorder, progressive supranuclear palsy, corticobasal degeneration, andfamilial frontotemporal dementia; a muscle disorder such ascardiomyopathy, myocarditis, Duchenne's muscular dystrophy, Becker'smuscular dystrophy, myotonic dystrophy, central core disease, nemalinemyopathy, centronuclear myopathy, lipid myopathy, mitochondrialmyopathy, infectious myositis, polymyositis, dermatomyositis, inclusionbody myositis, thyrotoxic myopathy, ethanol myopathy, angina,anaphylactic shock, arrhythmias, asthma, cardiovascular shock, Cushing'ssyndrome, hypertension, hypoglycemia, myocardial infarction, migraine,pheochromocytoma, and myopathies including encephalopathy, epilepsy,Kearns-Sayre syndrome, lactic acidosis, myoclonic disorder,ophthalmoplegia, and acid maltase deficiency (AMD, also known as Pompe'sdisease); an immunological disorder such as acquired immunodeficiencysyndrome (AIDS), Addison's disease, adult respiratory distress syndrome,allergies, ankylosing spondylitis, amyloidosis, anemia, asthma,atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis,autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED),bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopicdermatitis, dermatomyositis, diabetes mellitus, emphysema, episodiclymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythemanodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome,gout, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia,irritable bowel syndrome, multiple sclerosis, myasthenia gravis,myocardial or pericardial inflammation, osteoarthritis, osteoporosis,pancreatitis, polymyositis, psoriasis, Reiter's syndrome, rheumatoidarthritis, scleroderma, Sjögren's syndrome, systemic anaphylaxis,systemic lupus erythematosus, systemic sclerosis, thrombocytopenicpurpura, ulcerative colitis, uveitis, Werner syndrome, complications ofcancer, hemodialysis, and extracorporeal circulation, viral, bacterial,fungal, parasitic, protozoal, and helminthic infections, and trauma; anda cell proliferative disorder such as actinic keratosis,arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixedconnective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnalhemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia,and cancers including adenocarcinoma, leukemia, lymphoma, melanoma,myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of theadrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gallbladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung,muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands,skin, spleen, testis, thymus, thyroid, and uterus. The polynucleotidesequences encoding TRICH may be used in Southern or northern analysis,dot blot, or other membrane-based technologies; in PCR technologies; indipstick, pin, and multiformat ELISA-like assays; and in microarraysutilizing fluids or tissues from patients to detect altered TRICHexpression. Such qualitative or quantitative methods are well known inthe art.

[0258] In a particular aspect, the nucleotide sequences encoding TRICHmay be useful in assays that detect the presence of associateddisorders, particularly those mentioned above. The nucleotide sequencesencoding TRICH may be labeled by standard methods and added to a fluidor tissue sample from a patient under conditions suitable for theformation of hybridization complexes. After a suitable incubationperiod, the sample is washed and the signal is quantified and comparedwith a standard value. If the amount of signal in the patient sample issignificantly altered in comparison to a control sample then thepresence of altered levels of nucleotide sequences encoding TRICH in thesample indicates the presence of the associated disorder. Such assaysmay also be used to evaluate the efficacy of a particular therapeutictreatment regimen in animal studies, in clinical trials, or to monitorthe treatment of an individual patient.

[0259] In order to provide a basis for the diagnosis of a disorderassociated with expression of TRICH, a normal or standard profile forexpression is established. This may be accomplished by combining bodyfluids or cell extracts taken from normal subjects, either animal orhuman, with a sequence, or a fragment thereof, encoding TRICH, underconditions suitable for hybridization or amplification. Standardhybridization may be quantified by comparing the values obtained fromnormal subjects with values from an experiment in which a known amountof a substantially purified polynucleotide is used. Standard valuesobtained in this manner may be compared with values obtained fromsamples from patients who are symptomatic for a disorder. Deviation fromstandard values is used to establish the presence of a disorder.

[0260] Once the presence of a disorder is established and a treatmentprotocol is initiated, hybridization assays may be repeated on a regularbasis to determine if the level of expression in the patient begins toapproximate that which is observed in the normal subject. The resultsobtained from successive assays may be used to show the efficacy oftreatment over a period ranging from several days to months.

[0261] With respect to cancer, the presence of an abnormal amount oftranscript (either under- or overexpressed) in biopsied tissue from anindividual may indicate a predisposition for the development of thedisease, or may provide a means for detecting the disease prior to theappearance of actual clinical symptoms. A more definitive diagnosis ofthis type may allow health professionals to employ preventative measuresor aggressive treatment earlier thereby preventing the development orfurther progression of the cancer.

[0262] Additional diagnostic uses for oligonucleotides designed from thesequences encoding TRICH may involve the use of PCR. These oligomers maybe chemically synthesized, generated enzymatically, or produced invitro. Oligomers will preferably contain a fragment of a polynucleotideencoding TRICH, or a fragment of a polynucleotide complementary to thepolynucleotide encoding TRICH, and will be employed under optimizedconditions for identification of a specific gene or condition. Oligomersmay also be employed under less stringent conditions for detection orquantification of closely related DNA or RNA sequences.

[0263] In a particular aspect, oligonucleotide primers derived from thepolynucleotide sequences encoding TRICH may be used to detect singlenucleotide polymorphisms (SNPs). SNPs are substitutions, insertions anddeletions that are a frequent cause of inherited or acquired geneticdisease in humans. Methods of SNP detection include, but are not limitedto, single-stranded conformation polymorphism (SSCP) and fluorescentSSCP (fSSCP) methods. In SSCP, oligonucleotide primers derived from thepolynucleotide sequences encoding TRICH are used to amplify DNA usingthe polymerase chain reaction (PCR). The DNA may be derived, forexample, from diseased or normal tissue, biopsy samples, bodily fluids,and the like. SNPs in the DNA cause differences in the secondary andtertiary structures of PCR products in single-stranded form, and thesedifferences are detectable using gel electrophoresis in non-denaturinggels. In fSCCP, the oligonucleotide primers are fluorescently labeled,which allows detection of the amplimers in high-throughput equipmentsuch as DNA sequencing machines. Additionally, sequence databaseanalysis methods, termed in silico SNP (isSNP), are capable ofidentifying polymorphisms by comparing the sequence of individualoverlapping DNA fragments which assemble into a common consensussequence. These computer-based methods filter out sequence variationsdue to laboratory preparation of DNA and sequencing errors usingstatistical models and automated analyses of DNA sequence chromatograms.In the alternative, SNPs may be detected and characterized by massspectrometry using, for example, the high throughput MASSARRAY system(Sequenom, Inc., San Diego Calif.).

[0264] Methods which may also be used to quantify the expression ofTRICH include radiolabeling or biotinylating nucleotides,coamplification of a control nucleic acid, and interpolating resultsfrom standard curves. (See, e.g., Melby, P. C. et al. (1993) J. Immunol.Methods 159:235-244; Duplaa, C. et al. (1993) Anal. Biochem.212:229-236.) The speed of quantitation of multiple samples may beaccelerated by running the assay in a high-throughput format where theoligomer or polynucleotide of interest is presented in various dilutionsand a spectrophotometric or calorimetric response gives rapidquantitation.

[0265] In further embodiments, oligonucleotides or longer fragmentsderived from any of the polynucleotide sequences described herein may beused as elements on a microarray. The microarray can be used intranscript imaging techniques which monitor the relative expressionlevels of large numbers of genes simultaneously as described below. Themicroarray may also be used to identify genetic variants, mutations, andpolymorphisms. This information may be used to determine gene function,to understand the genetic basis of a disorder, to diagnose a disorder,to monitor progression/regression of disease as a function of geneexpression, and to develop and monitor the activities of therapeuticagents in the treatment of disease. In particular, this information maybe used to develop a pharmacogenomic profile of a patient in order toselect the most appropriate and effective treatment regimen for thatpatient. For example, therapeutic agents which are highly effective anddisplay the fewest side effects may be selected for a patient based onhis/her pharmacogenomic profile.

[0266] In another embodiment, TRICH, fragments of TRICH, or antibodiesspecific for TRICH may be used as elements on a microarray. Themicroarray may be used to monitor or measure protein-proteininteractions, drug-target interactions, and gene expression profiles, asdescribed above.

[0267] A particular embodiment relates to the use of the polynucleotidesof the present invention to generate a transcript image of a tissue orcell type. A transcript image represents the global pattern of geneexpression by a particular tissue or cell type. Global gene expressionpatterns are analyzed by quantifying the number of expressed genes andtheir relative abundance under given conditions and at a given time.(See Seilhamer et al., “Comparative Gene Transcript Analysis,” U.S. Pat.No. 5,840,484, expressly incorporated by reference herein.) Thus atranscript image may be generated by hybridizing the polynucleotides ofthe present invention or their complements to the totality oftranscripts or reverse transcripts of a particular tissue or cell type.In one embodiment, the hybridization takes place in high-throughputformat, wherein the polynucleotides of the present invention or theircomplements comprise a subset of a plurality of elements on amicroarray. The resultant transcript image would provide a profile ofgene activity.

[0268] Transcript images may be generated using transcripts isolatedfrom tissues, cell lines, biopsies, or other biological samples. Thetranscript image may thus reflect gene expression in vivo, as in thecase of a tissue or biopsy sample, or in vitro, as in the case of a cellline.

[0269] Transcript images which profile the expression of thepolynucleotides of the present invention may also be used in conjunctionwith in vitro model systems and preclinical evaluation ofpharmaceuticals, as well as toxicological testing of industrial andnaturally-occurring environmental compounds. All compounds inducecharacteristic gene expression patterns, frequently termed molecularfingerprints or toxicant signatures, which are indicative of mechanismsof action and toxicity (Nuwaysir, E. F. et al. (1999) Mol. Carcinog.24:153-159; Steiner, S. and N. L. Anderson (2000) Toxicol. Lett.112-113:467-471, expressly incorporated by reference herein). If a testcompound has a signature similar to that of a compound with knowntoxicity, it is likely to share those toxic properties. Thesefingerprints or signatures are most useful and refined when they containexpression information from a large number of genes and gene families.Ideally, a genome-wide measurement of expression provides the highestquality signature. Even genes whose expression is not altered by anytested compounds are important as well, as the levels of expression ofthese genes are used to normalize the rest of the expression data. Thenormalization procedure is useful for comparison of expression dataafter treatment with different compounds. While the assignment of genefunction to elements of a toxicant signature aids in interpretation oftoxicity mechanisms, knowledge of gene function is not necessary for thestatistical matching of signatures which leads to prediction oftoxicity. (See, for example, Press Release 00-02 from the NationalInstitute of Environmental Health Sciences, released Feb. 29, 2000,available at http://www.niehs.nih.gov/oc/news/toxchip.htm.) Therefore,it is important and desirable in toxicological screening using toxicantsignatures to include all expressed gene sequences.

[0270] In one embodiment, the toxicity of a test compound is assessed bytreating a biological sample containing nucleic acids with the testcompound. Nucleic acids that are expressed in the treated biologicalsample are hybridized with one or more probes specific to thepolynucleotides of the present invention, so that transcript levelscorresponding to the polynucleotides of the present invention may bequantified. The transcript levels in the treated biological sample arecompared with levels in an untreated biological sample. Differences inthe transcript levels between the two samples are indicative of a toxicresponse caused by the test compound in the treated sample.

[0271] Another particular embodiment relates to the use of thepolypeptide sequences of the present invention to analyze the proteomeof a tissue or cell type. The term proteome refers to the global patternof protein expression in a particular tissue or cell type. Each proteincomponent of a proteome can be subjected individually to furtheranalysis. Proteome expression patterns, or profiles, are analyzed byquantifying the number of expressed proteins and their relativeabundance under given conditions and at a given time. A profile of acell's proteome may thus be generated by separating and analyzing thepolypeptides of a particular tissue or cell type. In one embodiment, theseparation is achieved using two-dimensional gel electrophoresis, inwhich proteins from a sample are separated by isoelectric focusing inthe first dimension, and then according to molecular weight by sodiumdodecyl sulfate slab gel electrophoresis in the second dimension(Steiner and Anderson, supra). The proteins are visualized in the gel asdiscrete and uniquely positioned spots, typically by staining the gelwith an agent such as Coomassie Blue or silver or fluorescent stains.The optical density of each protein spot is generally proportional tothe level of the protein in the sample. The optical densities ofequivalently positioned protein spots from different samples, forexample, from biological samples either treated or untreated with a testcompound or therapeutic agent, are compared to identify any changes inprotein spot density related to the treatment. The proteins in the spotsare partially sequenced using, for example, standard methods employingchemical or enzymatic cleavage followed by mass spectrometry. Theidentity of the protein in a spot may be determined by comparing itspartial sequence, preferably of at least 5 contiguous amino acidresidues, to the polypeptide sequences of the present invention. In somecases, further sequence data may be obtained for definitive proteinidentification.

[0272] A proteomic profile may also be generated using antibodiesspecific for TRICH to quantify the levels of TRICH expression. In oneembodiment, the antibodies are used as elements on a microarray, andprotein expression levels are quantified by exposing the microarray tothe sample and detecting the levels of protein bound to each arrayelement (Lueking, A. et al. (1999) Anal. Biochem. 270:103-111; Mendoze,L. G. et al. (1999) Biotechniques 27:778-788). Detection may beperformed by a variety of methods known in the art, for example, byreacting the proteins in the sample with a thiol- or amino-reactivefluorescent compound and detecting the amount of fluorescence bound ateach array element.

[0273] Toxicant signatures at the proteome level are also useful fortoxicological screening, and should be analyzed in parallel withtoxicant signatures at the transcript level. There is a poor correlationbetween transcript and protein abundances for some proteins in sometissues (Anderson, N. L. and J. Seilhamer (1997) Electrophoresis18:533-537), so proteome toxicant signatures may be useful in theanalysis of compounds which do not significantly affect the transcriptimage, but which alter the proteomic profile. In addition, the analysisof transcripts in body fluids is difficult, due to rapid degradation ofmRNA, so proteomic profiling may be more reliable and informative insuch cases.

[0274] In another embodiment, the toxicity of a test compound isassessed by treating a biological sample containing proteins with thetest compound. Proteins that are expressed in the treated biologicalsample are separated so that the amount of each protein can bequantified. The amount of each protein is compared to the amount of thecorresponding protein in an untreated biological sample. A difference inthe amount of protein between the two samples is indicative of a toxicresponse to the test compound in the treated sample. Individual proteinsare identified by sequencing the amino acid residues of the individualproteins and comparing these partial sequences to the polypeptides ofthe present invention.

[0275] In another embodiment, the toxicity of a test compound isassessed by treating a biological sample containing proteins with thetest compound. Proteins from the biological sample are incubated withantibodies specific to the polypeptides of the present invention. Theamount of protein recognized by the antibodies is quantified. The amountof protein in the treated biological sample is compared with the amountin an untreated biological sample. A difference in the amount of proteinbetween the two samples is indicative of a toxic response to the testcompound in the treated sample.

[0276] Microarrays may be prepared, used, and analyzed using methodsknown in the art. (See, e.g., Brennan, T. M. et al. (1995) U.S. Pat.No.5,474,796; Schena, M. et al. (1996) Proc. Natl. Acad. Sci. USA93:10614-10619; Baldeschweiler et al. (1995) PCT applicationWO95/251116; Shalon, D. et al. (1995) PCT application WO95/35505;Heller, R. A. et al. (1997) Proc. Natl. Acad. Sci. USA 94:2150-2155; andHeller, M. J. et al. (1997) U.S. Pat. No. 5,605,662.) Various types ofmicroarrays are well known and thoroughly described in DNA Microarrays:A Practical Approach, M. Schena, ed. (1999) Oxford University Press,London, hereby expressly incorporated by reference.

[0277] In another embodiment of the invention, nucleic acid sequencesencoding TRICH may be used to generate hybridization probes useful inmapping the naturally occurring genomic sequence. Either coding ornoncoding sequences may be used, and in some instances, noncodingsequences may be preferable over coding sequences. For example,conservation of a coding sequence among members of a multi-gene familymay potentially cause undesired cross hybridization during chromosomalmapping. The sequences may be mapped to a particular chromosome, to aspecific region of a chromosome, or to artificial chromosomeconstructions, e.g., human artificial chromosomes (HACs), yeastartificial chromosomes (YACs), bacterial artificial chromosomes (BACs),bacterial P1 constructions, or single chromosome cDNA libraries. (See,e.g., Harrington, J. J. et al. (1997) Nat. Genet. 15:345-355; Price, C.M. (1993) Blood Rev. 7:127-134; and Trask, B. J. (1991) Trends Genet.7:149-154.) Once mapped, the nucleic acid sequences of the invention maybe used to develop genetic linkage maps, for example, which correlatethe inheritance of a disease state with the inheritance of a particularchromosome region or restriction fragment length polymorphism (RFLP).(See, for example, Lander, E. S. and D. Botstein (1986) Proc. Natl.Acad. Sci. USA 83:7353-7357.)

[0278] Fluorescent in situ hybridization (FISH) may be correlated withother physical and genetic map data. (See, e.g., Heinz-Ulrich, et al.(1995) in Meyers, supra, pp. 965-968.) Examples of genetic map data canbe found in various scientific journals or at the Online MendelianInheritance in Man (OMIM) World Wide Web site. Correlation between thelocation of the gene encoding TRICH on a physical map and a specificdisorder, or a predisposition to a specific disorder, may help definethe region of DNA associated with that disorder and thus may furtherpositional cloning efforts.

[0279] In situ hybridization of chromosomal preparations and physicalmapping techniques, such as linkage analysis using establishedchromosomal markers, may be used for extending genetic maps. Often theplacement of a gene on the chromosome of another mammalian species, suchas mouse, may reveal associated markers even if the exact chromosomallocus is not known. This information is valuable to investigatorssearching for disease genes using positional cloning or other genediscovery techniques. Once the gene or genes responsible for a diseaseor syndrome have been crudely localized by genetic linkage to aparticular genomic region, e.g., ataxia-telangiectasia to 11q22-23, anysequences mapping to that area may represent associated or regulatorygenes for further investigation. (See, e.g., Gatti, R. A. et al. (1988)Nature 336:577-580.) The nucleotide sequence of the instant inventionmay also be used to detect differences in the chromosomal location dueto translocation, inversion, etc., among normal, carrier, or affectedindividuals.

[0280] In another embodiment of the invention, TRICH, its catalytic orimmunogenic fragments, or oligopeptides thereof can be used forscreening libraries of compounds in any of a variety of drug screeningtechniques. The fragment employed in such screening may be free insolution, affixed to a solid support, borne on a cell surface, orlocated intracellularly. The formation of binding complexes betweenTRICH and the agent being tested may be measured.

[0281] Another technique for drug screening provides for high throughputscreening of compounds having suitable binding affinity to the proteinof interest. (See, e.g., Geysen, et al. (1984) PCT applicationWO84/03564.) In this method, large numbers of different small testcompounds are synthesized on a solid substrate. The test compounds arereacted with TRICH, or fragments thereof, and washed. Bound TRICH isthen detected by methods well known in the art. Purified TRICH can alsobe coated directly onto plates for use in the aforementioned drugscreening techniques. Alternatively, non-neutralizing antibodies can beused to capture the peptide and immobilize it on a solid support.

[0282] In another embodiment, one may use competitive drug screeningassays in which neutralizing antibodies capable of binding TRICHspecifically compete with a test compound for binding TRICH. In thismanner, antibodies can be used to detect the presence of any peptidewhich shares one or more antigenic determinants with TRICH.

[0283] In additional embodiments, the nucleotide sequences which encodeTRICH may be used in any molecular biology techniques that have yet tobe developed, provided the new techniques rely on properties ofnucleotide sequences that are currently known, including, but notlimited to, such properties as the triplet genetic code and specificbase pair interactions.

[0284] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. The following preferred specificembodiments are, therefore, to be construed as merely illustrative, andnot limitative of the remainder of the disclosure in any way whatsoever.

[0285] The disclosures of all patents, applications, and publicationsmentioned above and below, including U.S. Ser. No. 60/208,424, U.S. Ser.No. 60/209,001, U.S. Ser. No. 60/210,588, U.S. Ser. No. 60/212,335, U.S.Ser. No. 60/213,747, and U.S. Ser. No. 60/215,391, are hereby expresslyincorporated by reference.

EXAMPLES

[0286] 1. Construction of cDNA Libraries

[0287] Incyte cDNAs were derived from cDNA libraries described in theLIFESEQ GOLD database (Incyte Genomics, Palo Alto Calif.) and shown inTable 4, column 5. Some tissues were homogenized and lysed inguanidinium isothiocyanate, while others were homogenized and lysed inphenol or in a suitable mixture of denaturants, such as TRIZOL (LifeTechnologies), a monophasic solution of phenol and guanidineisothiocyanate. The resulting lysates were centrifuged over CsClcushions or extracted with chloroform. RNA was precipitated from thelysates with either isopropanol or sodium acetate and ethanol, or byother routine methods.

[0288] Phenol extraction and precipitation of RNA were repeated asnecessary to increase RNA purity. In some cases, RNA was treated withDNase. For most libraries, poly(A)+ RNA was isolated using oligod(T)-coupled paramagnetic particles (Promega), OLIGOTEX latex particles(QIAGEN, Chatsworth Calif.), or an OLIGOTEX mRNA purification kit(QIAGEN). Alternatively, RNA was isolated directly from tissue lysatesusing other RNA isolation kits, e.g., the POLY(A)PURE mRNA purificationkit (Ambion, Austin Tex.).

[0289] In some cases, Stratagene was provided with RNA and constructedthe corresponding cDNA libraries. Otherwise, cDNA was synthesized andcDNA libraries were constructed with the UNIZAP vector system(Stratagene) or SUPERSCRIPT plasmid system (Life Technologies), usingthe recommended procedures or similar methods known in the art. (See,e.g., Ausubel, 1997, supra, units 5.1-6.6.) Reverse transcription wasinitiated using oligo d(T) or random primers. Synthetic oligonucleotideadapters were ligated to double stranded cDNA, and the cDNA was digestedwith the appropriate restriction enzyme or enzymes. For most libraries,the cDNA was size-selected (300-1000 bp) using SEPHACRYL S1000,SEPHAROSE CL2B, or SEPHAROSE CL4B column chromatography (AmershamPharmacia Biotech) or preparative agarose gel electrophoresis. cDNAswere ligated into compatible restriction enzyme sites of the polylinkerof a suitable plasmid, e.g., PBLUESCRIPT plasmid (Stratagene), PSPORT1plasmid (Life Technologies), PCDNA2.1 plasmid (Invitrogen, CarlsbadCalif.), PBK-CMV plasmid (Stratagene), or pINCY (Incyte Genomics, PaloAlto Calif.), or derivatives thereof. Recombinant plasmids weretransformed into competent E. coli cells including XL1-Blue,XL1-BlueMRF, or SOLR from Stratagene or DH5α, DH10B, or ElectroMAX DH10Bfrom Life Technologies.

[0290] II. Isolation of cDNA Clones

[0291] Plasmids obtained as described in Example I were recovered fromhost cells by in vivo excision using the UNIZAP vector system(Stratagene) or by cell lysis. Plasmids were purified using at least oneof the following: a Magic or WIZARD Minipreps DNA purification system(Promega); an AGTC Miniprep purification kit (Edge Biosystems,Gaithersburg Md.); and QIAWELL 8 Plasmid, QIAWELL 8 Plus Plasmid,QIAWELL 8 Ultra Plasmid purification systems or the R.E.A.L PREP 96plasmid purification kit from QIAGEN. Following precipitation, plasmidswere resuspended in 0.1 ml of distilled water and stored, with orwithout lyophilization, at 4° C.

[0292] Alternatively, plasmid DNA was amplified from host cell lysatesusing direct link PCR in a high-throughput format (Rao, V. B. (1994)Anal. Biochem. 216:1-14). Host cell lysis and thermal cycling steps werecarried out in a single reaction mixture. Samples were processed andstored in 384-well plates, and the concentration of amplified plasmidDNA was quantified fluorometrically using PICOGREEN dye (MolecularProbes, Eugene Oreg.) and a FLUOROSKAN II fluorescence scanner(Labsystems Oy, Helsinki, Finland).

[0293] III. Sequencing and Analysis

[0294] Incyte cDNA recovered in plasmids as described in Example II weresequenced as follows. Sequencing reactions were processed using standardmethods or high-throughput instrumentation such as the ABI CATALYST 800(Applied Biosystems) thermal cycler or the PTC-200 thermal cycler (MJResearch) in conjunction with the HYDRA microdispenser (RobbinsScientific) or the MICROLAB 2200 (Hamilton) liquid transfer system. cDNAsequencing reactions were prepared using reagents provided by AmershamPharmacia Biotech or supplied in ABI sequencing kits such as the ABIPRISM BIGDYE Terminator cycle sequencing ready reaction kit (AppliedBiosystems). Electrophoretic separation of cDNA sequencing reactions anddetection of labeled polynucleotides were carried out using the MEGABACE1000 DNA sequencing system (Molecular Dynamics); the ABI PRISM 373 or377 sequencing system (Applied Biosystems) in conjunction with standardABI protocols and base calling software; or other sequence analysissystems known in the art. Reading frames within the cDNA sequences wereidentified using standard methods (reviewed in Ausubel, 1997, supra,unit 7.7). Some of the cDNA sequences were selected for extension usingthe techniques disclosed in Example VIII.

[0295] The polynucleotide sequences derived from Incyte cDNAs werevalidated by removing vector, linker, and poly(A) sequences and bymasking ambiguous bases, using algorithms and programs based on BLAST,dynamic programming, and dinucleotide nearest neighbor analysis. TheIncyte cDNA sequences or translations thereof were then queried againsta selection of public databases such as the GenBank primate, rodent,mammalian, vertebrate, and eukaryote databases, and BLOCKS, PRINTS,DOMO, PRODOM, and hidden Markov model (HM)-based protein familydatabases such as PFAM. (HMM is a probabilistic approach which analyzesconsensus primary structures of gene families. See, for example, Eddy,S. R. (1996) Curr. Opin. Struct. Biol. 6:361-365.) The queries wereperformed using programs based on BLAST, FASTA, BLIMPS, and HMMER. TheIncyte cDNA sequences were assembled to produce full lengthpolynucleotide sequences. Alternatively, GenBank cDNAs, GenBank ESTs,stitched sequences, stretched sequences, or Genscan-predicted codingsequences (see Examples IV and V) were used to extend Incyte cDNAassemblages to full length. Assembly was performed using programs basedon Phred, Phrap, and Consed, and cDNA assemblages were screened for openreading frames using programs based on GeneMark, BLAST, and FASTA. Thefull length polynucleotide sequences were translated to derive thecorresponding full length polypeptide sequences. Alternatively, apolypeptide of the invention may begin at any of the methionine residuesof the full length translated polypeptide. Full length polypeptidesequences were subsequently analyzed by querying against databases suchas the GenBank protein databases (genpept), SwissProt, BLOCKS, PRINTS,DOMO, PRODOM, Prosite, and hidden Markov model (HMM)-based proteinfamily databases such as PFAM. Full length polynucleotide sequences arealso analyzed using MACDNASIS PRO software (Hitachi SoftwareEngineering, South San Francisco Calif.) and LASERGENE software(DNASTAR). Polynucleotide and polypeptide sequence alignments aregenerated using default parameters specified by the CLUSTAL algorithm asincorporated into the MEGALIGN multisequence alignment program(DNASTAR), which also calculates the percent identity between alignedsequences.

[0296] Table 7 summarizes the tools, programs, and algorithms used forthe analysis and assembly of Incyte cDNA and full length sequences andprovides applicable descriptions, references, and threshold parameters.The first column of Table 7 shows the tools, programs, and algorithmsused, the second column provides brief descriptions thereof, the thirdcolumn presents appropriate references, all of which are incorporated byreference herein in their entirety, and the fourth column presents,where applicable, the scores, probability values, and other parametersused to evaluate the strength of a match between two sequences (thehigher the score or the lower the probability value, the greater theidentity between two sequences).

[0297] The programs described above for the assembly and analysis offull length polynucleotide and polypeptide sequences were also used toidentify polynucleotide sequence fragments from SEQ ID NO: 28-54.Fragments from about 20 to about 4000 nucleotides which are useful inhybridization and amplification technologies are described in Table 4,column 4.

[0298] IV. Identification and Editing of Coding Sequences from GenomicDNA

[0299] Putative transporters and ion channels were initially identifiedby running the Genscan gene identification program against publicgenomic sequence databases (e.g., gbpri and gbhtg). Genscan is ageneral-purpose gene identification program which analyzes genomic DNAsequences from a variety of organisms (See Burge, C. and S. Karlin(1997) J. Mol. Biol. 268:78-94, and Burge, C. and S. Karlin (1998) Curr.Opin. Struct. Biol. 8:346-354). The program concatenates predicted exonsto form an assembled cDNA sequence extending from a methionine to a stopcodon. The output of Genscan is a FASTA database of polynucleotide andpolypeptide sequences. The maximum range of sequence for Genscan toanalyze at once was set to 30 kb. To determine which of these Genscanpredicted cDNA sequences encode transporters and ion channels, theencoded polypeptides were analyzed by querying against PFAM models fortransporters and ion channels. Potential transporters and ion channelswere also identified by homology to Incyte cDNA sequences that had beenannotated as transporters and ion channels. These selectedGenscan-predicted sequences were then compared by BLAST analysis to thegenpept and gbpri public databases. Where necessary, theGenscan-predicted sequences were then edited by comparison to the topBLAST hit from genpept to correct errors in the sequence predicted byGenscan, such as extra or omitted exons. BLAST analysis was also used tofind any Incyte cDNA or public cDNA coverage of the Genscan-predictedsequences, thus providing evidence for transcription. When Incyte cDNAcoverage was available, this information was used to correct or confirmthe Genscan predicted sequence. Full length polynucleotide sequenceswere obtained by assembling Genscan-predicted coding sequences withIncyte cDNA sequences and/or public cDNA sequences using the assemblyprocess described in Example III. Alternatively, full lengthpolynucleotide sequences were derived entirely from edited or uneditedGenscan-predicted coding sequences.

[0300] V. Assembly of Genomic Sequence Data with cDNA Sequence Data

[0301] “Stitched” Sequences

[0302] Partial cDNA sequences were extended with exons predicted by theGenscan gene identification program described in Example IV. PartialcDNAs assembled as described in Example III were mapped to genomic DNAand parsed into clusters containing related cDNAs and Genscan exonpredictions from one or more genomic sequences. Each cluster wasanalyzed using an algorithm based on graph theory and dynamicprogramming to integrate cDNA and genomic information, generatingpossible splice variants that were subsequently confirmed, edited, orextended to create a full length sequence. Sequence intervals in whichthe entire length of the interval was present on more than one sequencein the cluster were identified, and intervals thus identified wereconsidered to be equivalent by transitivity. For example, if an intervalwas present on a cDNA and two genomic sequences, then all threeintervals were considered to be equivalent. This process allowsunrelated but consecutive genomic sequences to be brought together,bridged by cDNA sequence. Intervals thus identified were then “stitched”together by the stitching algorithm in the order that they appear alongtheir parent sequences to generate the longest possible sequence, aswell as sequence variants. Linkages between intervals which proceedalong one type of parent sequence (cDNA to cDNA or genomic sequence togenomic sequence) were given preference over linkages which changeparent type (cDNA to genomic sequence). The resultant stitched sequenceswere translated and compared by BLAST analysis to the genpept and gbpripublic databases. Incorrect exons predicted by Genscan were corrected bycomparison to the top BLAST hit from genpept. Sequences were furtherextended with additional cDNA sequences, or by inspection of genomicDNA, when necessary.

[0303] “Stretched” Sequences

[0304] Partial DNA sequences were extended to full length with analgorithm based on BLAST analysis. First, partial cDNAs assembled asdescribed in Example III were queried against public databases such asthe GenBank primate, rodent, mammalian, vertebrate, and eukaryotedatabases using the BLAST program. The nearest GenBank protein homologwas then compared by BLAST analysis to either Incyte cDNA sequences orGenScan exon predicted sequences described in Example IV. A chimericprotein was generated by using the resultant high-scoring segment pairs(HSPs) to map the translated sequences onto the GenBank protein homolog.Insertions or deletions may occur in the chimeric protein with respectto the original GenBank protein homolog. The GenBank protein homolog,the chimeric protein, or both were used as probes to search forhomologous genomic sequences from the public human genome databases.Partial DNA sequences were therefore “stretched” or extended by theaddition of homologous genomic sequences. The resultant stretchedsequences were examined to determine whether it contained a completegene.

[0305] VI. Chromosomal Mapping of TRICH Encoding Polynucleotides

[0306] The sequences which were used to assemble SEQ ID NO: 28-54 werecompared with sequences from the Incyte LIFESEQ database and publicdomain databases using BLAST and other implementations of theSmith-Waterman algorithm. Sequences from these databases that matchedSEQ ID NO: 28-54 were assembled into clusters of contiguous andoverlapping sequences using assembly algorithms such as Phrap (Table 7).Radiation hybrid and genetic mapping data available from publicresources such as the Stanford Human Genome Center (SHGC), WhiteheadInstitute for Genome Research (WIGR), and Généthon were used todetermine if any of the clustered sequences had been previously mapped.Inclusion of a mapped sequence in a cluster resulted in the assignmentof all sequences of that cluster, including its particular SEQ ID NO:,to that map location.

[0307] Map locations are represented by ranges, or intervals, of humanchromosomes. The map position of an interval, in centiMorgans, ismeasured relative to the terminus of the chromosome's p-arm. (ThecentiMorgan (cM) is a unit of measurement based on recombinationfrequencies between chromosomal markers. On average, 1 cM is roughlyequivalent to 1 megabase (Mb) of DNA in humans, although this can varywidely due to hot and cold spots of recombination.) The cM distances arebased on genetic markers mapped by Gédéthon which provide boundaries forradiation hybrid markers whose sequences were included in each of theclusters. Human genome maps and other resources available to the public,such as the NCBI “GeneMap'99” World Wide Web site(http://www.ncbi.nlm.nih.gov/genemap/), can be employed to determine ifpreviously identified disease genes map within or in proximity to theintervals indicated above.

[0308] In this manner, SEQ ID NO: 8 was mapped to chromosome 12 withinthe interval from 137.50 to 160.90 centiMorgans.

[0309] VII. Analysis of Polynucleotide Expression

[0310] Northern analysis is a laboratory technique used to detect thepresence of a transcript of a gene and involves the hybridization of alabeled nucleotide sequence to a membrane on which RNAs from aparticular cell type or tissue have been bound. (See, e.g., Sambrook,supra, ch. 7; Ausubel (1995) supra, ch. 4 and 16.)

[0311] Analogous computer techniques applying BLAST were used to searchfor identical or related molecules in cDNA databases such as GenBank orLIFESEQ (Incyte Genomics). This analysis is much faster than multiplemembrane-based hybridizations. In addition, the sensitivity of thecomputer search can be modified to determine whether any particularmatch is categorized as exact or similar. The basis of the search is theproduct score, which is defined as:$\frac{{BLAST}\quad {Score} \times {Percent}\quad {Identity}}{5 \times {minimum}\left\{ {{{lenght}\left( {{Seq}.\quad 1} \right)},{{length}\left( {{Seq}.\quad 2} \right)}} \right\}}$

[0312] The product score takes into account both the degree ofsimilarity between two sequences and the length of the sequence match.The product score is a normalized value between 0 and 100, and iscalculated as follows: the BLAST score is multiplied by the percentnucleotide identity and the product is divided by (5 times the length ofthe shorter of the two sequences). The BLAST score is calculated byassigning a score of +5 for every base that matches in a high-scoringsegment pair (HSP), and −4 for every mismatch. Two sequences may sharemore than one HSP (separated by gaps). If there is more than one HSP,then the pair with the highest BLAST score is used to calculate theproduct score. The product score represents a balance between fractionaloverlap and quality in a BLAST alignment. For example, a product scoreof 100 is produced only for 100% identity over the entire length of theshorter of the two sequences being compared. A product score of 70 isproduced either by 100% identity and 70% overlap at one end, or by 88%identity and 100% overlap at the other. A product score of 50 isproduced either by 100% identity and 50% overlap at one end, or 79%identity and 100% overlap.

[0313] Alternatively, polynucleotide sequences encoding TRICH areanalyzed with respect to the tissue sources from which they werederived. For example, some full length sequences are assembled, at leastin part, with overlapping Incyte cDNA sequences (see Example III). EachcDNA sequence is derived from a cDNA library constructed from a humantissue. Each human tissue is classified into one of the followingorgan/tissue categories: cardiovascular system; connective tissue;digestive system; embryonic structures; endocrine system; exocrineglands; genitalia, female; genitalia, male; germ cells; hemic and immunesystem; liver; musculoskeletal system; nervous system; pancreas;respiratory system; sense organs; skin; stomatognathic system;unclassified/mixed; or urinary tract. The number of libraries in eachcategory is counted and divided by the total number of libraries acrossall categories. Similarly, each human tissue is classified into one ofthe following disease/condition categories: cancer, cell line,developmental, inflammation, neurological, trauma, cardiovascular,pooled, and other, and the number of libraries in each category iscounted and divided by the total number of libraries across allcategories. The resulting percentages reflect the tissue- anddisease-specific expression of cDNA encoding TRICH. cDNA sequences andcDNA library/tissue information are found in the LIFESEQ GOLD database(Incyte Genomics, Palo Alto Calif.).

[0314] VIII. Extension of TRICH Encoding Polynucleotides

[0315] Full length polynucleotide sequences were also produced byextension of an appropriate fragment of the full length molecule usingoligonucleotide primers designed from this fragment. One primer wassynthesized to initiate 5′ extension of the known fragment, and theother primer was synthesized to initiate 3′ extension of the knownfragment. The initial primers were designed using OLIGO 4.06 software(National Biosciences), or another appropriate program, to be about 22to 30 nucleotides in length, to have a GC content of about 50% or more,and to anneal to the target sequence at temperatures of about 68° C. toabout 72° C. Any stretch of nucleotides which would result in hairpinstructures and primer-primer dimerizations was avoided.

[0316] Selected human cDNA libraries were used to extend the sequence.If more than one extension was necessary or desired, additional ornested sets of primers were designed.

[0317] High fidelity amplification was obtained by PCR using methodswell known in the art. PCR was performed in 96-well plates using thePTC-200 thermal cycler (MJ Research, Inc.). The reaction mix containedDNA template, 200 nmol of each primer, reaction buffer containing Mg²⁺,(NH₄)₂SO₄, and 2-mercaptoethanol, Taq DNA polymerase (Amersham PharmaciaBiotech), ELONGASE enzyme (Life Technologies), and Pfu DNA polymerase(Stratagene), with the following parameters for primer pair PCI A andPCI B: Step 1: 94° C., 3 min; Step 2: 94° C., 15 sec; Step 3: 60° C., 1min; Step 4: 68° C., 2 min; Step 5: Steps 2, 3, and 4 repeated 20 times;Step 6: 68° C., 5 min; Step 7: storage at 4° C. In the alternative, theparameters for primer pair T7 and SK+ were as follows: Step 1: 94° C., 3min; Step 2: 94° C., 15 sec; Step 3: 57° C., 1 min; Step 4: 68° C., 2min; Step 5: Steps 2, 3, and 4 repeated 20 times; Step 6: 68° C., 5 min;Step 7: storage at 4° C.

[0318] The concentration of DNA in each well was determined bydispensing 100 μl PICOGREEN quantitation reagent (0.25% (v/v) PICOGREEN;Molecular Probes, Eugene Oreg.) dissolved in 1×TE and 0.5 μl ofundiluted PCR product into each well of an opaque fluorimeter plate(Corning Costar, Acton Mass.), allowing the DNA to bind to the reagent.The plate was scanned in a Fluoroskan II (Labsystems Oy, Helsinki,Finland) to measure the fluorescence of the sample and to quantify theconcentration of DNA. A 5 μl to 10 μl aliquot of the reaction mixturewas analyzed-by electrophoresis on a 1% agarose gel to determine whichreactions were successful in extending the sequence.

[0319] The extended nucleotides were desalted and concentrated,transferred to 384-well plates, digested with CviJI cholera virusendonuclease (Molecular Biology Research, Madison Wis.), and sonicatedor sheared prior to religation into pUC 18 vector (Amersham PharmaciaBiotech). For shotgun sequencing, the digested nucleotides wereseparated on low concentration (0.6 to 0.8%) agarose gels, fragmentswere excised, and agar digested with Agar ACE (Promega). Extended cloneswere religated using T4 ligase (New England Biolabs, Beverly Mass.) intopUC 18 vector (Amersham Pharmacia Biotech), treated with Pfu DNApolymerase (Stratagene) to fill-in restriction site overhangs, andtransfected into competent E. coli cells. Transformed cells wereselected on antibiotic-containing media, and individual colonies werepicked and cultured overnight at 37° C. in 384-well plates in LB/2×carbliquid media.

[0320] The cells were lysed, and DNA was amplified by PCR using Taq DNApolymerase (Amersham Pharmacia Biotech) and Pfu DNA polymerase(Stratagene) with the following parameters: Step 1: 94° C., 3 min; Step2: 94° C., 15 sec; Step 3: 60° C., 1 min; Step 4: 72° C., 2 min; Step 5:steps 2, 3, and 4 repeated 29 times; Step 6: 72° C., 5 min; Step 7:storage at 4° C. DNA was quantified by PICOGREEN reagent (MolecularProbes) as described above. Samples with low DNA recoveries werereamplified using the same conditions as described above. Samples werediluted with 20% dimethysulfoxide (1:2, v/v), and sequenced usingDYENAMIC energy transfer sequencing primers and the DYENAMIC DIRECT kit(Amersham Pharmacia Biotech) or the ABI PRISM BIGDYE Terminator cyclesequencing ready reaction kit (Applied Biosystems).

[0321] In like manner, full length polynucleotide sequences are verifiedusing the above procedure or are used to obtain 5′ regulatory sequencesusing the above procedure along with oligonucleotides designed for suchextension, and an appropriate genomic library.

[0322] IX. Labeling and Use of Individual Hybridization Probes

[0323] Hybridization probes derived from SEQ ID NO: 28-54 are employedto screen cDNAs, genomic DNAs, or mRNAs. Although the labeling ofoligonucleotides, consisting of about 20 base pairs, is specificallydescribed, essentially the same procedure is used with larger nucleotidefragments. Oligonucleotides are designed using state-of-the-art softwaresuch as OLIGO 4.06 software (National Biosciences) and labeled bycombining 50 pmol of each oligomer, 250 μCi of [γ-³²P] adenosinetriphosphate (Amersham Pharmacia Biotech), and T4 polynucleotide kinase(DuPont NEN, Boston Mass.). The labeled oligonucleotides aresubstantially purified using a SEPHADEX G-25 superfine size exclusiondextran bead column (Amersham Pharmacia Biotech). An aliquot containing10⁷ counts per minute of the labeled probe is used in a typicalmembrane-based hybridization analysis of human genomic DNA digested withone of the following endonucleases: Ase I, Bgl II, Eco RI, Pst I, Xba I,or Pvu II (DuPont NEN).

[0324] The DNA from each digest is fractionated on a 0.7% agarose geland transferred to nylon membranes (Nytran Plus, Schleicher & Schuell,Durham N.H.). Hybridization is carried out for 16 hours at 40° C. Toremove nonspecific signals, blots are sequentially washed at roomtemperature under conditions of up to, for example, 0.1×saline sodiumcitrate and 0.5% sodium dodecyl sulfate. Hybridization patterns arevisualized using autoradiography or an alternative imaging means andcompared.

[0325] X. Microarrays

[0326] The linkage or synthesis of array elements upon a microarray canbe achieved utilizing photolithography, piezoelectric printing (ink-jetprinting, See, e.g., Baldeschweiler, supra.), mechanical microspottingtechnologies, and derivatives thereof. The substrate in each of theaforementioned technologies should be uniform and solid with anon-porous surface (Schena (1999), supra). Suggested substrates includesilicon, silica, glass slides, glass chips, and silicon wafers.Alternatively, a procedure analogous to a dot or slot blot may also beused to arrange and link elements to the surface of a substrate usingthermal, UV, chemical, or mechanical bonding procedures. A typical arraymay be produced using available methods and machines well known to thoseof ordinary skill in the art and may contain any appropriate number ofelements. (See, e.g., Schena, M. et al. (1995) Science 270:467-470;Shalon, D. et al. (1996) Genome Res. 6:639-645; Marshall, A. and J.Hodgson (1998) Nat. Biotechnol. 16:27-31.)

[0327] Full length cDNAs, Expressed Sequence Tags (ESTs), or fragmentsor oligomers thereof may comprise the elements of the microarray.Fragments or oligomers suitable for hybridization can be selected usingsoftware well known in the art such as LASERGENE software (DNASTAR). Thearray elements are hybridized with polynucleotides in a biologicalsample. The polynucleotides in the biological sample are conjugated to afluorescent label or other molecular tag for ease of detection. Afterhybridization, nonhybridized nucleotides from the biological sample areremoved, and a fluorescence scanner is used to detect hybridization ateach array element. Alternatively, laser desorbtion and massspectrometry may be used for detection of hybridization. The degree ofcomplementarity and the relative abundance of each polynucleotide whichhybridizes to an element on the microarray may be assessed. In oneembodiment, microarray preparation and usage is described in detailbelow.

[0328] Tissue or Cell Sample Preparation

[0329] Total RNA is isolated from tissue samples using the guanidiniumthiocyanate method and poly(A)⁺ RNA is purified using the oligo-(dT)cellulose method. Each poly(A)⁺ RNA sample is reverse transcribed usingMMLV reverse-transcriptase, 0.05 pg/μl oligo-(dT) primer (21 mer), 1×first strand buffer, 0.03 units/μl RNase inhibitor, 500 μM dATP, 500 μMdGTP, 500 μM dTTP, 40 μM dCTP, 40 μM dCTP-Cy3 (BDS) or dCTP-Cy5(Amersham Pharmacia Biotech). The reverse transcription reaction isperformed in a 25 ml volume containing 200 ng poly(A)⁺ RNA withGEMBRIGHT kits (Incyte). Specific control poly(A)⁺ RNAs are synthesizedby in vitro transcription from non-coding yeast genomic DNA. Afterincubation at 37° C. for 2 hr, each reaction sample (one with Cy3 andanother with Cy5 labeling) is treated with 2.5 ml of 0.5M sodiumhydroxide and incubated for 20 minutes at 85° C. to the stop thereaction and degrade the RNA. Samples are purified using two successiveCHROMA SPIN 30 gel filtration spin columns (CLONTECH Laboratories, Inc.(CLONTECH), Palo Alto Calif.) and after combining, both reaction samplesare ethanol precipitated using 1 ml of glycogen (1 mg/ml), 60 ml sodiumacetate, and 300 ml of 100% ethanol. The sample is then dried tocompletion using a SpeedVAC (Savant Instruments Inc., Holbrook N.Y.) andresuspended in 14 μl 5×SSC/0.2% SDS.

[0330] Microarray Preparation

[0331] Sequences of the present invention are used to generate arrayelements. Each array element is amplified from bacterial cellscontaining vectors with cloned cDNA inserts. PCR amplification usesprimers complementary to the vector sequences flanking the cDNA insert.Array elements are amplified in thirty cycles of PCR from an initialquantity of 1-2 ng to a final quantity greater than 5 μg. Amplifiedarray elements are then purified using SEPHACRYL-400 (Amersham PharmaciaBiotech).

[0332] Purified array elements are immobilized on polymer-coated glassslides. Glass microscope slides (Corning) are cleaned by ultrasound in0.1% SDS and acetone, with extensive distilled water washes between andafter treatments. Glass slides are etched in 4% hydrofluoric acid (VWRScientific Products Corporation (VWR), West Chester Pa.), washedextensively in distilled water, and coated with 0.05% aminopropyl silane(Sigma) in 95% ethanol. Coated slides are cured in a 110° C. oven.

[0333] Array elements are applied to the coated glass substrate using aprocedure described in U.S. Pat. No. 5,807,522, incorporated herein byreference. 1 μl of the array element DNA, at an average concentration of100 ng/μl, is loaded into the open capillary printing element by ahigh-speed robotic apparatus. The apparatus then deposits about 5 nl ofarray element sample per slide.

[0334] Micro arrays are UV-crosslinked using a STRATALINKERUV-crosslinker (Stratagene). Microarrays are washed at room temperatureonce in 0.2% SDS and three times in distilled water. Non-specificbinding sites are blocked by incubation of microarrays in 0.2% casein inphosphate buffered saline (PBS) (Tropix, Inc., Bedford Mass.) for 30minutes at 60° C. followed by washes in 0.2% SDS and distilled water asbefore.

[0335] Hybridization

[0336] Hybridization reactions contain 9 μl of sample mixture consistingof 0.2 μg each of Cy3 and Cy5 labeled cDNA synthesis products in 5×SSC,0.2% SDS hybridization buffer. The sample mixture is heated to 65° C.for 5 minutes and is aliquoted onto the microarray surface and coveredwith an 1.8 cm² coverslip. The arrays are transferred to a waterproofchamber having a cavity just slightly larger than a microscope slide.The chamber is kept at 100% humidity internally by the addition of 140μl of 5×SSC in a corner of the chamber. The chamber containing thearrays is incubated for about 6.5 hours at 60° C. The arrays are washedfor 10 min at 45° C. in a first wash buffer (1×SSC, 0.1% SDS), threetimes for 10 minutes each at 45° C. in a second wash buffer (0.1×SSC),and dried.

[0337] Detection

[0338] Reporter-labeled hybridization complexes are detected with amicroscope equipped with an Innova 70 mixed gas 10 W laser (Coherent,Inc., Santa Clara Calif.) capable of generating spectral lines at 488 nmfor excitation of Cy3 and at 632 nm for excitation of Cy5. Theexcitation laser light is focused on the array using a 20× microscopeobjective (Nikon, Inc., Melville N.Y.). The slide containing the arrayis placed on a computer-controlled X-Y stage on the microscope andraster-scanned past the objective. The 1.8 cm×1.8 cm array used in thepresent example is scanned with a resolution of 20 micrometers.

[0339] In two separate scans, a mixed gas multiline laser excites thetwo fluorophores sequentially. Emitted light is split, based onwavelength, into two photomultiplier tube detectors (PMT R1477,Hamamatsu Photonics Systems, Bridgewater N.J.) corresponding to the twofluorophores. Appropriate filters positioned between the array and thephotomultiplier tubes are used to filter the signals. The emissionmaxima of the fluorophores used are 565 nm for Cy3 and 650 nm for Cy5.Each array is typically scanned twice, one scan per fluorophore usingthe appropriate filters at the laser source, although the apparatus iscapable of recording the spectra from both fluorophores simultaneously.

[0340] The sensitivity of the scans is typically calibrated using thesignal intensity generated by a cDNA control species added to the samplemixture at a known concentration. A specific location on the arraycontains a complementary DNA sequence, allowing the intensity of thesignal at that location to be correlated with a weight ratio ofhybridizing species of 1:100,000. When two samples from differentsources (e.g., representing test and control cells), each labeled with adifferent fluorophore, are hybridized to a single array for the purposeof identifying genes that are differentially expressed, the calibrationis done by labeling samples of the calibrating cDNA with the twofluorophores and adding identical amounts of each to the hybridizationmixture.

[0341] The output of the photomultiplier tube is digitized using a12-bit RTI-835H analog-to-digital (A/D) conversion board (AnalogDevices, Inc., Norwood Mass.) installed in an IBM-compatible PCcomputer. The digitized data are displayed as an image where the signalintensity is mapped using a linear 20-color transformation to apseudocolor scale ranging from blue (low signal) to red (high signal).The data is also analyzed quantitatively. Where two differentfluorophores are excited and measured simultaneously, the data are firstcorrected for optical crosstalk (due to overlapping emission spectra)between the fluorophores using each fluorophore's emission spectrum.

[0342] A grid is superimposed over the fluorescence signal image suchthat the signal from each spot is centered in each element of the grid.The fluorescence signal within each element is then integrated to obtaina numerical value corresponding to the average intensity of the signal.The software used for signal analysis is the GEMTOOLS gene expressionanalysis program (Incyte).

[0343] XI. Complementary Polynucleotides

[0344] Sequences complementary to the TRICH-encoding sequences, or anyparts thereof, are used to detect, decrease, or inhibit expression ofnaturally occurring TRICH. Although use of oligonucleotides comprisingfrom about 15 to 30 base pairs is described, essentially the sameprocedure is used with smaller or with larger sequence fragments.Appropriate oligonucleotides are designed using OLIGO 4.06 software(National Biosciences) and the coding sequence of TRICH. To inhibittranscription, a complementary oligonucleotide is designed from the mostunique 5′ sequence and used to prevent promoter binding to the codingsequence. To inhibit translation, a complementary oligonucleotide isdesigned to prevent ribosomal binding to the TRICH-encoding transcript.

[0345] XII. Expression of TRICH

[0346] Expression and purification of TRICH is achieved using bacterialor virus-based expression systems. For expression of TRICH in bacteria,cDNA is subcloned into an appropriate vector containing an antibioticresistance gene and an inducible promoter that directs high levels ofcDNA transcription Examples of such promoters include, but are notlimited to, the trp-lac (tac) hybrid promoter and the T5 or T7bacteriophage promoter in conjunction with the lac operator regulatoryelement. Recombinant vectors are transformed into suitable bacterialhosts, e.g., BL21 (DE3). Antibiotic resistant bacteria express TRICHupon induction with isopropyl beta-D-thiogalactopyranoside (IPTG).Expression of TRICH in eukaryotic cells is achieved by infecting insector mammalian cell lines with recombinant Autographica californicanuclear polyhedrosis virus (AcMNPV), commonly known as baculovirus. Thenonessential polyhedrin gene of baculovirus is replaced with cDNAencoding TRICH by either homologous recombination or bacterial-mediatedtransposition involving transfer plasmid intermediates. Viralinfectivity is maintained and the strong polyhedrin promoter drives highlevels of cDNA transcription. Recombinant baculovirus is used to infectSpodoptera frugiperda (Sf9) insect cells in most cases, or humanhepatocytes, in some cases. Infection of the latter requires additionalgenetic modifications to baculovirus. (See Engelhard, E. K. et al.(1994) Proc. Natl. Acad. Sci. USA 91:3224-3227; Sandig, V. et al. (1996)Hum. Gene Ther. 7:1937-1945.)

[0347] In most expression systems. TRICH is synthesized as a fusionprotein with, e.g., glutathione S-transferase (GST) or a peptide epitopetag, such as FLAG or 6-His, permitting rapid, single-step,affinity-based purification of recombinant fusion protein from crudecell lysates. GST, a 26-kilodalton enzyme from Schistosoma japonicum,enables the purification of fusion proteins on immobilized glutathioneunder conditions that maintain protein activity and antigenicity(Amersham Pharmacia Biotech). Following purification, the GST moiety canbe proteolytically cleaved from TRICH at specifically engineered sites.FLAG, an 8-amino acid peptide, enables immunoaffinity purification usingcommercially available monoclonal and polyclonal anti-FLAG antibodies(Eastman Kodak). 6-His, a stretch of six consecutive histidine residues,enables purification on metal-chelate resins (QIAGEN). Methods forprotein expression and purification are discussed in Ausubel (1995,supra, ch. 10 and 16). Purified TRICH obtained by these methods can beused directly in the assays shown in Examples XVI, XVII, and XVIII,where applicable.

[0348] XIII. Functional Assays

[0349] TRICH function is assessed by expressing the sequences encodingTRICH at physiologically elevated levels in mammalian cell culturesystems. cDNA is subcloned into a mammalian expression vector containinga strong promoter that drives high levels of cDNA expression. Vectors ofchoice include PCMV SPORT (Life Technologies) and PCR3.1 (Invitrogen,Carlsbad Calif.), both of which contain the cytomegalovirus promoter.5-10 μg of recombinant vector are transiently transfected into a humancell line, for example, an endothelial or hematopoietic cell line, usingeither liposome formulations or electroporation. 1-2 μg of an additionalplasmid containing sequences encoding a marker protein areco-transfected. Expression of a marker protein provides a means todistinguish transfected cells from nontransfected cells and is areliable predictor of cDNA expression from the recombinant vector.Marker proteins of choice include, e.g., Green Fluorescent Protein (GFP;Clontech), CD64, or a CD64-GFP fusion protein. Flow cytometry (FCM), anautomated, laser optics-based technique, is used to identify transfectedcells expressing GFP or CD64-GFP and to evaluate the apoptotic state ofthe cells and other cellular properties. FCM detects and quantifies theuptake of fluorescent molecules that diagnose events preceding orcoincident with cell death. These events include changes in nuclear DNAcontent as measured by staining of DNA with propidium iodide; changes incell size and granularity as measured by forward light scatter and 90degree side light scatter; down-regulation of DNA synthesis as measuredby decrease in bromodeoxyuridine uptake; alterations in expression ofcell surface and intracellular proteins as measured by reactivity withspecific antibodies; and alterations in plasma membrane composition asmeasured by the binding of fluorescein-conjugated Annexin V protein tothe cell surface. Methods in flow cytometry are discussed in Ormerod, M.G. (1994) Flow Cytometry, Oxford, New York N.Y.

[0350] The influence of TRICH on gene expression can be assessed usinghighly purified populations of cells transfected with sequences encodingTRICH and either CD64 or CD64-GFP. CD64 and CD64-GFP are expressed onthe surface of transfected cells and bind to conserved regions of humanimmunoglobulin G (IgG). Transfected cells are efficiently separated fromnontransfected cells using magnetic beads coated with either human IgGor antibody against CD64 (DYNAL, Lake Success N.Y.). mRNA can bepurified from the cells using methods well known by those of skill inthe art. Expression of mRNA encoding TRICH and other genes of interestcan be analyzed by northern analysis or microarray techniques.

[0351] XIV. Production of TRICH Specific Antibodies

[0352] TRICH substantially purified using polyacrylamide gelelectrophoresis (PAGE; see, e.g., Harrington, M. G. (1990) MethodsEnzymol. 182:488-495), or other purification techniques, is used toimmunize rabbits and to produce antibodies using standard protocols.

[0353] Alternatively, the TRICH amino acid sequence is analyzed usingLASERGENE software (DNASTAR) to determine regions of highimmunogenicity, and a corresponding oligopeptide is synthesized and usedto raise antibodies by means known to those of skill in the art Methodsfor selection of appropriate epitopes, such as those near the C-terminusor in hydrophilic regions are well described in the art. (See, e.g.,Ausubel, 1995, supra, ch. 11.)

[0354] Typically, oligopeptides of about 15 residues in length aresynthesized using an ABI 431A peptide synthesizer (Applied Biosystems)using FMOC chemistry and coupled to KLH (Sigma-Aldrich, St. Louis Mo.)by reaction with N-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) toincrease immunogenicity. (See, e.g., Ausubel, 1995, supra.) Rabbits areimmunized with the oligopeptide-KLH complex in complete Freund'sadjuvant. Resulting antisera are tested for antipeptide and anti-TRICHactivity by, for example, binding the peptide or TRICH to a substrate,blocking with 1% BSA, reacting with rabbit antisera, washing, andreacting with radio-iodinated goat anti-rabbit IgG.

[0355] XV. Purification of Naturally Occurring TRICH using SpecificAntibodies

[0356] Naturally occurring or recombinant TRICH is substantiallypurified by immunoaffinity chromatography using antibodies specific forTRICH. An immunoaffinity column is constructed by covalently couplinganti-TRICH antibody to an activated chromatographic resin, such asCNBr-activated SEPHAROSE (Amersham Pharmacia Biotech). After thecoupling, the resin is blocked and washed according to themanufacturer's instructions.

[0357] Media containing TRICH are passed over the immunoaffinity column,and the column is washed under conditions that allow the preferentialabsorbance of TRICH (e.g., high ionic strength buffers in the presenceof detergent). The column is eluted under conditions that disruptantibody/TRICH binding (e.g., a buffer of pH 2 to pH 3, or a highconcentration of a chaotrope, such as urea or thiocyanate ion), andTRICH is collected.

[0358] XVI. Identification of Molecules which Interact with TRICH

[0359] Molecules which interact with TRICH may include transportersubstrates, agonists or antagonists, modulatory proteins such as Gβγproteins (Reimann, supra) or proteins involved in TRICH localization orclustering such as MAGUKs (Craven, supra). TRICH, or biologically activefragments thereof, are labeled with ¹²⁵I Bolton-Hunter reagent. (See,e.g., Bolton A. E. and W. M. Hunter (1973) Biochem. J. 133:529-539.)Candidate molecules previously arrayed in the wells of a multi-wellplate are incubated with the labeled TRICH, washed, and any wells withlabeled TRICH complex are assayed. Data obtained using differentconcentrations of TRICH are used to calculate values for the number,affinity, and association of TRICH with the candidate molecules.

[0360] Alternatively, proteins that interact with TRICH are isolatedusing the yeast 2-hybrid system (Fields, S. and O. Song (1989) Nature340:245-246). TRICH, or fragments thereof, are expressed as fusionproteins with the DNA binding domain of Gal4 or lexA, and potentialinteracting proteins are expressed as fusion proteins with an activationdomain. Interactions between the TRICH fusion protein and the TRICHinteracting proteins (fusion proteins with an activation domain)reconstitute a transactivation function that is observed by expressionof a reporter gene. Yeast 2-hybrid systems are commercially available,and methods for use of the yeast 2-hybrid system with ion channelproteins are discussed in Niethammer, M. and M. Sheng (1998, Meth.Enzymol. 293:104-122).

[0361] TRICH may also be used in the PATHCALLING process (CuraGen Corp.,New Haven Conn.) which employs the yeast two-hybrid system in ahigh-throughput manner to determine all interactions between theproteins encoded by two large libraries of genes (Nandabalan, K et al.(2000) U.S. Pat. No. 6,057,101).

[0362] Potential TRICH agonists or antagonists may be tested foractivation or inhibition of TRICH ion channel activity using the assaysdescribed in section XVIII.

[0363] XVII. Demonstration of TRICH Activity

[0364] Ion channel activity of TRICH is demonstrated using anelectrophysiological assay for ion conductance. TRICH can be expressedby transforming a mammalian cell line such as COS7, HeLa or CHO with aeukaxyotic expression vector encoding TRICH. Eukaryotic expressionvectors are commercially available, and the techniques to introduce theminto cells are well known to those skilled in the art. A second plasmidwhich expresses any one of a number of marker genes, such asβ-galactosidase, is co-transformed into the cells to allow rapididentification of those cells which have taken up and expressed theforeign DNA. The cells are incubated for 48-72 hours aftertransformation under conditions appropriate for the cell line to allowexpression and accumulation of TRICH and 13-galactosidase.

[0365] Transformed cells expressing β-galactosidase are stained bluewhen a suitable colorimetric substrate is added to the culture mediaunder conditions that are well known in the art Stained cells are testedfor differences in membrane conductance by electrophysiologicaltechniques that are well known in the art. Untransformed cells, and/orcells transformed with either vector sequences alone or β-galactosidasesequences alone, are used as controls and tested in parallel. Cellsexpressing TRICH will have higher anion or cation conductance relativeto control cells. The contribution of TRICH to conductance can beconfirmed by incubating the cells using antibodies specific for TRICH.The antibodies will bind to the extracellular side of TRICH, therebyblocking the pore in the ion channel, and the associated conductance.

[0366] Alternatively, ion channel activity of TRICH is measured ascurrent flow across a TRICH-containing Xenopus laevis oocyte membraneusing the two-electrode voltage-clamp technique (Ishi et al., supra;Jegla, T. and L. Salkoff (1997) J. Neurosci. 17:32-44). TRICH issubcloned into an appropriate Xenopus oocyte expression vector, such aspBF, and 0.5-5 ng of mRNA is injected into mature stage IV oocytes.Injected oocytes are incubated at 18° C. for 1-5 days. Inside-outmacropatches are excised into an intracellular solution containing 116mM K-gluconate, 4 mM KCl, and 10 mM Hepes (pH 7.2). The intracellularsolution is supplemented with varying concentrations of the TRICHmediator, such as cAMP, cGMP, or Ca⁺² (in the form of CaCl₂), whereappropriate. Electrode resistance is set at 2-5 MΩ and electrodes arefilled with the intracellular solution lacking mediator. Experiments areperformed at room temperature from a holding potential of 0 mV. Voltageramps (2.5 s) from −100 to 100 mV are acquired at a sampling frequencyof 500 Hz. Current measured is proportional to the activity of TRICH inthe assay.

[0367] In particular the activity of TRICH-10 is measured as cationconductance in the presence of heat, the activity of TRICH-12 ismeasured as anion conductance in the presence of GABA, the activity ofTRICH-13 is measured as Na⁺ conductance, the activity of TRICH-21 ismeasured as voltage-gated Cl− conductance, the activity of TRICH-22 ismeasured as Ca²⁺ conductance, the activity of TRICH-24 is measured asvoltage-gated Ca²⁺ conductance, the activity of TRICH-26 is measured asK⁺ conductance in the presence of cyclic nucleotides, and the activityof TRICH-27 is measured as Cl⁻ conductance.

[0368] Transport activity of TRICH is assayed by measuring uptake oflabeled substrates into Xenopus laevis oocytes. Oocytes at stages V andVI are injected with TRICH mRNA (10 ng per oocyte) and incubated for 3days at 18° C. in OR2 medium (82.5 mM NaCl, 2.5 mM KCl, 1 mM CaCl₂, 1 mMMgCl₂, 1 mM Na₂HPO₄, 5 mM Hepes, 3.8 mM NaOH, 50 μg/ml gentamycin, pH7.8) to allow expression of TRICH. Oocytes are then transferred tostandard uptake medium (100 mM NaCl, 2 mM KCl, 1 mM CaCl₂, 1 mM MgCl₂,10 mM Hepes/Tris pH 7.5). Uptake of various substrates (e.g., aminoacids, sugars, drugs, ions, and neurotransmitters) is initiated byadding labeled substrate (e.g. radiolabeled with ³H, fluorescentlylabeled with rhodamine, etc.) to the oocytes. After incubating for 30minutes, uptake is terminated by washing the oocytes three times inNa⁺-free medium, measuring the incorporated label, and comparing withcontrols. TRICH activity is proportional to the level of internalizedlabeled substrate. In particular, test substrates include organiccations for TRICH-9, carnitine and acylcarnitine for TRICH-11, galactoseand other sugars for TRICH-14, glucose for TRICH-15, monocarboxylate forTRICH-16, cations for TRICH-17, estramustine and related drugs forTRICH-18, amino acids for TRICH-19, glucose for TRICH-20, sugars forTRICH-23, and glucose or fructose for TRICH-25.

[0369] In the alternative, TRICH transport activity can be demonstratedthrough the use of a ligand mixing assay that is used to measuretransport from early to late endosomal compartments in X. laevisoocytes. Ovaries are dissected from adult female X. laevis, and oocytesare isolated. (Mukhopadhyay A. et al. (1997) J. Cell. Biol. 136(6):1227-1237). Oocytes are pulsed with 2 mg/ml avidin for 5 hrs at 18° C.,washed, then incubated for 16 hrs to allow avidin to transport to a latecompartment. The oocytes are then incubated with 1 mg/mlbiotin-horseradish peroxidase (HRP) for 30 minutes at 18° C. to labelearly endocytic compartments. Varying amounts of TRICH are injected intothe oocytes, and the oocytes are incubated at 18° C. Oocytes arecollected at several time points after TRICH injection, washed, andlysed in 100 μl of phosphate-buffered saline containing 0.3% TritonX-100, 0.2% methylbenzethorium chloride, and 400 μg/ml of BSA-biotin asa scavenger. Finally, the lysates are centrifuged for 30 seconds in amicrofuge, and the avidin-biotin complexes are immunoprecipitated usinganti-avidin antibody-coated plates by incubation at 4° C. overnight. Theplates are washed at least 5 times to remove unbound proteins. Transportfrom the early endosomes to the late compartments is quantified bymeasuring the amount of immunoprecipitated HRP; increased transport dueto TRICH is quantitated by comparison with control oocytes. Potentialinhibitors of proton-dependent histidine transport such as dipeptidesand tripeptides can subsequently be tested in the expression systemdescribed above (Yamashita, T. et al. (1997) J. Cell. Biol. 136(6):1227-1237).

[0370] ATPase activity associated with TRICH can be measured byhydrolysis of radiolabeled ATP-[γ-³²P], separation of the hydrolysisproducts by chromatographic methods, and quantitation of the recovered³²P using a scintillation counter. The reaction mixture containsATP-[γ-³²P] and varying amounts of TRICH in a suitable buffer incubatedat 37° C. for a suitable period of time. The reaction is terminated byacid precipitation with trichloroacetic acid and then neutralized withbase, and an aliquot of the reaction mixture is subjected to membrane orfilter paper-based chromatography to separate the reaction products. Theamount of ³²P liberated is counted in a scintillation counter. Theamount of radioactivity recovered is proportional to the ATPase activityof TRICH in the assay.

[0371] XVIII. Identification of TRICH Agonists and Antagonists

[0372] TRICH is expressed in a eukaryotic cell line such as CHO (ChineseHamster Ovary) or HEK (Human Embryonic Kidney) 293. Ion channel activityof the transformed cells is measured in the presence and absence ofcandidate agonists or antagonists. Ion channel activity is assayed usingpatch clamp methods well known in the art or as described in ExampleXVII. Alternatively, ion channel activity is assayed using fluorescenttechniques that measure ion flux across the cell membrane (Velicelebi,G. et al. (1999) Meth. Enzymol. 294:20-47; West, M. R. and C. R. Molloy(1996) Anal. Biochem. 241:51-58). These assays may be adapted forhigh-throughput screening using microplates. Changes in internal ionconcentration are measured using fluorescent dyes such as the Ca²⁺indicator Fluo-4 AM, sodium-sensitive dyes such as SBFI and sodiumgreen, or the Cl⁻ indicator MQAE (all available from Molecular Probes)in combination with the FLIPR fluorimetric plate reading system(Molecular Devices). In a more generic version of this assay, changes inmembrane potential caused by ionic flux across the plasma membrane aremeasured using oxonyl dyes such as DiBAC₄ (Molecular Probes). DiBAC₄equilibrates between the extracellular solution and cellular sitesaccording to the cellular membrane potential. The dye's fluorescenceintensity is 20-fold greater when bound to hydrophobic intracellularsites, allowing detection of DiBAC₄ entry into the cell (Gonzalez, J. E.and P. A. Negulescu (1998) Curr. Opin. Biotechnol. 9:624-631). Candidateagonists or antagonists may be selected from known ion channel agonistsor antagonists, peptide libraries, or combinatorial chemical libraries.

[0373] Various modifications and variations of the described methods andsystems of the invention will be apparent to those skilled in the artwithout departing from the scope and spirit of the invention. Althoughthe invention has been described in connection with certain embodiments,it should be understood that the invention as claimed should not beunduly limited to such specific embodiments. Indeed, variousmodifications of the described modes for carrying out the inventionwhich are obvious to those skilled in molecular biology or relatedfields are intended to be within the scope of the following claims.TABLE 1 Polypep- Incyte Incyte tide SEQ Incyte PolynucleotidePolynucleotide Project ID ID NO: Polypeptide ID SEQ ID NO: ID 7475353 17475353CD1 28 7475353CB1 3107278 2 3107278CD1 29 3107278CB1 7473394 37473394CD1 30 7473394CB1 7473900 4 7473900CD1 31 7473900CB1 7475045 57475045CD1 32 7475045CB1 7475611 6 7475611CD1 33 7475611CB1 7475617 77475617CD1 34 7475617CB1 7473314 8 7473314CD1 35 7473314CB1 70356714 970356714CD1 36 70356714CB1 7611491 10 7611491CD1 37 7611491CB1 171968 11171968CD1 38 171968CB1 257274 12 257274CD1 39 257274CB1 6355991 136355991CD1 40 6355991CB1 70035348 14 70035348CD1 41 70035348CB1 747253915 7472539CD1 42 7472539CB1 817477 16 817477CD1 43 817477CB1 1442166 171442166CD1 44 1442166CB1 2311751 18 2311751CD1 45 2311751CB1 7472537 197472537CD1 46 7472537CB1 7472546 20 7472546CD1 47 7472546CB1 7474202 217474202CD1 48 7474202CB1 7476280 22 7476280CD1 49 7476280CB1 1713377 231713377CD1 50 1713377CB1 5842557 24 5842557CD1 51 5842557CB1 7476643 257476643CD1 52 7476643CB1 7611651 26 7611651CD1 53 7611651CB1 2522075 272522075CD1 54 2522075CB1

[0374] TABLE 2 Incyte Polypeptide Polypeptide GenBank ID Probability SEQID NO: ID NO: score GenBank Homolog 1 7475353CD1 g2982567 0 ABCtransporter [Rattus norvegicus] (Hirsch-Ernst, K. I. et al. (1998)Molecular cDNA cloning and tissue distribution of mRNA encoding a novelATP-binding cassette (ABC) half-transporter. Biochem. Biophys. Res.Commun. 249: 151-155.) 2 3107278CD1 g6010763 5.00E−180 ion transporterprotein [Rattus norvegicus] 3 7473394CD1 g12724309 0 sugar ABCtransporter ATP binding protein [Lactococcus lactis subsp. lactis](Bolotin, A. et al. (2001) The Complete Genome Sequence of the LacticAcid Bacterium Lactococcus lactis ssp. lactis IL1403. Genome Res. 11:731-753.) g4980593 2.20E−131 sugar ABC transporter, ATP-binding protein[Thermotoga maritima] 4 7473900CD1 g5565862 8.10E−141 ornithinetransporter [Homo sapiens] (Camacho, J. A. et al. (1999)Hyperornithinaemia- hyperammonaemia-homocitrullinuria syndrome is causedby mutations in a gene encoding a mitochondrial ornithine transporter.Nat. Genet. 22: 151-158.) 5 7475045CD1 g5701943 3.50E−44 mitochondrialoxaloacetate transport protein [Saccharomyces cerevisiae] (Palmieri, L.et al. (1999) Identification of the yeast mitochondrial transporter foroxaloacetate and sulfate. J. Biol. Chem. 274: 22184-22190.) 6 7475611CD1g2808786 3.10E−61 cobalt transport system ATP binding protein[Streptomyces coelicolor] 7 7475617CD1 g2944233 1.20E−239sodium-hydrogen exchanger 6 [Homo sapiens] (Numata, M. et al. (1998)Identification of a mitochondrial Na+/H+ exchanger. J. Biol. Chem. 273:6951-6959.) 8 7473314CD1 g2208839 1.80E−262 peptide/histidinetransporter [Rattus norvegicus] (Yamashita, T. et al. (1997) Cloning andfunctional expression of a brain peptide/histidine transporter. J. Biol.Chem. 272: 10205-10211.) 9 70356714CD1 g7707622 0 organic aniontransporter 4 [Homo sapiens] (Cha, S. H. et al. (2000) Molecular cloningand characterization of multispecific organic anion transporter 4expressed in the placenta. J. Biol. Chem. 275: 4507-4512.) g26967095.00E−141 RST (Renal specific transporter) [Mus musculus] (Mori, K. etal. (1997) Kidney-specific expression of a novel mouse organic cationtransporter-like protein. FEBS Lett. 417: 371-374.) 10 7611491CD1g11055322 0 vanilloid receptor-related osmotically activated channel[Homo sapiens] (Liedtke, W. et al. (2000) Vanilloid receptor-relatedosmotically activated channel (VR-OAC), a candidate vertebrateosmoreceptor. Cell 103: 525-535.) g2570933 6.90E−135 vanilloid receptorsubtype 1 [Rattus norvegicus] (Caterina, M. J. et al. (1997) Thecapsaicin receptor: a heat-activated ion channel in the pain pathway.Nature 389: 816-824.) 11 171968CD1 g13027346 2.00E−33 putativecarnitine/acylcarnitine translocase [Oryza sativa] g4239974 6.90E−25mCAC (mitochondrial carnitine/acylcarnitine transporter) [Mus musculus]12 257274CD1 g292040 1.30E−39 GABA-alpha receptor beta-3 subunit [Homosapiens] 13 6355991CD1 g12642270 0 voltage-gated sodium channel alphasubunit SCN1A [Homo sapiens] g1041089 0 Na+ channel [Rattus norvegicus](Noda, M. and Numa, S. (1987) Structure and function of sodium channel.J. Recept. Res. 7: 467-497.) 14 70035348CD1 g1789312 1.30E−53galactose-proton symport of transport system [Escherichia coli] 157472539CD1 g9588428 0 dJ1024N4.1 (novel Sodium: solute symporter familymember similar to SLC5A1 (SGLT1)) [Homo sapiens] g286259 8.90E−174Sodium/glucose cotransporter [Rattus norvegicus] 16 817477CD1 g60933228.00E−63 monocarboxylate transporter MCT3 [Homo sapiens] (Yoon, H., etal. (1999) Cloning of the human monocarboxylate transporter MCT3 gene:localization to chromosome 22q12.3-q13.2. Genomics 60: 366-370.) 171442166CD1 g12248394 0 cation-transporting ATPase [Mus musculus] 182311751CD1 g495259 0 abc2 [Mus musculus] (Laing N. M. et al. (1998)Amplification of the ATP- binding cassette 2 transporter gene isfunctionally linked with enhanced efflux of estramustine in ovariancarcinoma cells. Cancer Res. 58: 1332-1337.) 19 7472537CD1 g74069502.00E−137 N system amino acids transporter NAT-1 [Mus musculus] (Gu, S.et al. (2000) Identification and characterization of an amino acidtransporter expressed differentially in liver. Proc. Natl. Acad. Sci.U.S.A. 97: 3230-3235.) 20 7472546CD1 g9588428 0 dJ1024N4.1 (novelSodium: solute symporter family member similar to SLC5A1 (SGLT1)) [Homosapiens] g338055 2.70E−197 Na+/glucose cotransporter [Homo sapiens](Hediger, M. A. et al. (1989) Homology of the human intestinalNa+/glucose and Escherichia coli Na+/proline cotransporters. Proc. Natl.Acad. Sci. U.S.A. 86: 5748-5752.) 21 7474202CD1 g1217689 0 ClC chloridechannel ClC-K2 (human, kidney) [Homo sapiens] (Takeuchi, Y. et al.(1995) Cloning, tissue distribution, and intrarenal localization of ClCchloride channels in human kidney. Kidney Int. 48: 1497-1503.) 227476280CD1 g4877836 0 TRP2 (transient receptor potential) [Rattusnorvegicus] (Liman, E. R. et al. (1999) TRP2: a candidate transductionchannel for mammalian pheromone sensory signaling. Proc. Natl. Acad.Sci. U.S.A. 96: 5791-5796.) 23 1713377CD1 g3874275 2.20E−76 Similarityto Yeast low-afinity glucose transporter HXT4 [Caenorhabditis elegans]24 5842557CD1 g4586963 1.10E−23 voltage-gated calcium channel [Rattusnorvegicus] (Ishibashi, K. et al. (2000) Molecular cloning of a novelform (Two-repeat) protein related to voltage- gated sodium and calciumchannels. Biochem. Biophys. Res. Commun. 270: 370-376.) 25 7476643CD1g9230651 0 facilitative glucose transporter family member GLUT9 [Homosapiens] (Phay, J. E. et al. (2000) Cloning and expression analysis of anovel member of the facilitative glucose transporter family, SLC2A9(GLUT9). Genomics 66: 217-220.) g183298 3.70E−113 GLUT5 protein [Homosapiens] (Kayano, T. et al. (1990) Human facilitative glucosetransporters. Isolation, functional characterization, and genelocalization of cDNAs encoding an isoform (GLUT5) expressed in smallintestine, kidney, muscle, and adipose tissue and an unusual glucosetransporter pseudogene-like sequence (GLUT6). J. Biol. Chem. 265:13276-13282.) 26 7611651CD1 g2745729 0 potassium channel [Rattusnorvegicus] (Shi, W. et al. (1997) Identification of two nervoussystem-specific members of the erg potassium channel gene family. J.Neurosci. 17: 9423-9432.) 27 2522075CD1 g7592636 1.60E−183 Parchorin[Oryctolagus cuniculus] (Nishizawa, T. et al. (2000) (Molecular cloningand characterization of a novel chloride intracellular channel-relatedprotein, parchorin, expressed in water- secreting cells. J. Biol. Chem.275: 11164-11173.)

[0375] TABLE 3 SEQ Incyte Amino Potential Potential Analytical IDPolypeptide Acid Phosphorylation Glycosylation Signature Sequences,Methods and NO: ID Residues Sites Sites Domains and Motifs Databases 17475353CD1 842 S111 S34 S342 N447 N498 ABC TRANSPORTERS FAMILYBLAST_DOMO S357 S598 S661 N677 N775 DM00008|Q02592|583-793: R589-G800S728 S755 T238 ABC TRANSPORTER PD130117: BLAST_PRODOM T294 T341 T394M1-L263 T462 T605 T679 ABC transporters family BL00211A: L621-BLIMPS_BLOCKS T759 T831 T97 I632 BL00211B: L727-D758 ABC transportersfamily signature ProfileScan atp_bind_transport.prf: A708-D758Transmembrane domain: HMMER F186-G203, Y386-S406 ABC transportertransmembrane region. HMMER_PFAM ABC_membrane: V265-L544 ABC transporterHMMER_PFAM ABC_tran: G616-G800 Abc_Transporter Motifs L727-I741Atp_Gtp_A Motifs G623-S630 2 3107278CD1 461 S141 S153 S185 N404 N54Signal peptide: SPSCAN S306 S406 T162 M1-S52 T429 T448 T60 Transmembranedomains: HMMER I39-F58; S59-T75; V119-F138; G270-N290; V341-T360;F373-L392 Sugar (and other) transporter domain: HMMER_PFAM S5-E409(Score = −64.7; E−value = 1.5e−4) Sugar transport proteins signatureBLIMPS_BLOCKS BL00216: F58-M107 Sugar transport motif: MOTIFS T22-S38 37473394CD1 485 S236 S462 S52 N3 N367 Signal peptide: SPSCAN T10 T166T191 N460 M1-G53 T239 T316 T324 ABC transporter domain: HMMER_PFAM T345T386 T89 G24-G210; G277-G471 ABC transporters family signatureBLIMPS_BLOCKS BL00211: L29-L40; L396-D427 ABC transporters familysignature: PROFILESCAN L378-D427 ATPBINDING PUTATIVE ATPASE RIBOSE/BLAST_PRODOM GALACTOSE ABC TRANSPORTER PROTEIN MGLA PD035715: K241-K311ABC TRANSPORTERS FAMILY BLAST_DOMO DM00008|P47365|6-219: M1-R208;E260-I468 ABC transporter motif: MOTIFS L396-V410 ATP/GTP binding site(P-loop): MOTIFS G31-S38 4 7473900CD1 301 S143 S200 S203 Mitochondrialcarrier proteins domain: HMMER_PFAM S290 T136 T32 Q8-M294 T39Mitochondrial energy transfer protein BLIMPS_BLOCKS signature BL00215:L214-Q238 Mitochondrial energy transfer proteins PROFILESCAN signature:A10-G59; Q101-K163; K204-A276 PROTEIN TRANSPORT TRANSMEMBRANEBLAST_PRODOM REPEAT MITOCHONDRION CARRIER MEMBRANE INNER MITOCHONDRIALADP/ATP PD000117: Y44-S241 MITOCHONDRIAL ENERGY TRANSFER BLAST_DOMOPROTEINS DM00026|S55056|202-289: L207-E288 Mitochondrial carrier proteinmotif: MOTIFS P126-L134; P229-I237 5 7475045CD1 304 S190 S231 T225Signal peptide: HMMER M1-A20 Mitochondrial carrier proteins domain:HMMER_PFAM P5-A296 Mitochondrial energy transfer proteins BLIMPS_BLOCKSsignature BL00215: V11-Q35; I258-G270 Mitochondrial energy transferproteins PROFILESCAN signature: A7-V60; W206-I258 PROTEIN TRANSPORTTRANSMEMBRANE BLAST_PRODOM REPEAT MITOCHONDRION CARRIER MEMBRANE INNERMITOCHONDRIAL ADP/ATP PD000117: D9-Y91; T100-K294 MITOCHONDRIAL ENERGYTRANSFER BLAST_DOMO PROTEINS DM00026|P32332|233-312: L210-L295Mitochondrial carrier protein motif: MOTIFS P26-L34 6 7475611CD1 278S144 S2 S29 S44 N27 N42 ABC transporter domain: HMMER_PFAM S56 T260G33-G218 ABC transporters family signature BLIMPS_BLOCKS BL00211:I38-L49; L143-D174 ABC transporters family signature: PROFILESCANS124-D174 COBALT TRANSPORT SYSTEM ATP BINDING BLAST_PRODOM PROTEINMEMBRANE ASSOCIATED ATPASE PD029284: D186-S269 ABC TRANSPORTERS FAMILYBLAST_DOMO DM00008|Q05596|2-210: L7-L204 ABC transporter motif: MOTIFSL143-V157 ATP/GTP binding site (P-loop): MOTIFS G40-T47 7 7475617CD1 673S13 S145 S191 N348 N519 Transmembrane domains: HMMER S207 S493 S532 N536N621 V19-F38; L155-I173; L275-T296; S636 S641 S642 N92 M457-T477 S659S71 S94 Sodium/hydrogen exchanger family domain: HMMER_PFAM T101 T124T538 L21-V487 T6 T605 T612 Na+/H+ exchanger signature PR01084:BLIMPS_PRINTS T631 T80 V129-F140; G143-S157; I158-T166; G203-T213 Na+/H+exchanger isoform PR01088: BLIMPS_PRINTS E11-I35; W36-I54; Y55-Q81;E115-E128; S246-D263; A265-M284; T476-W502; G535-D553; P559-Q587;V588-D615 +TRANSPORT EXCHANGER NA PD01672: BLIMPS_(—) V129-M177 PRODOMSODIUMHYDROGEN EXCHANGER 6 BLAST_(—) MYELOBLAST KIAA0267 PD177855:PRODOM G474-E494; Y504-N672 do BETA; EXCHANGER; NA; BLAST_DOMODM02572|P48764|10-734: E11-L63; D118-R486 8 7473314CD1 576 S134 S269S278 N139 N218 PTR2 FAMILY PROTON/OLIGOPEPTIDE BLAST-DOMO S289 S293 S297N355 N435 SYMPORTERS DM01990: S400 S423 S510 A35-N525, P305-C529,V311-M517, S519 S553 S573 A34-G524 T169 T190 T369 TRANSPORTER TRANSPORTBLAST-PRODOM T572 TRANSMEMBRANE PEPTIDE OLIGOPEPTIDE PROTEIN SYMPORTISOFORM H+/PEPTIDE COTRANSPORTER PD001550: T307-S499 PEPTIDE/HISTIDINETRANSPORTER PD127516: BLAST-PRODOM F494-R575 PTR2A PEPTIDE TRANSPORTERTRANSPORT BLAST-PRODOM TRANSMEMBRANE PD170949: D447-S499 PTR2 familyproton/oligopeptide BLIMPS-BLOCKS transporter BL01022E: E464-S499,E43-L61, A73-A118, G159-V182, F194-I206 PTR2 Proton-dependentoligopeptide HMMER-PFAM transport (POT) family peptide transportersignature: A102-S495 PTR2 family proton/oligopeptide MOTIFS symporterssignature 2: F194-I206 Multicopper Oxidase signature 1: MOTIFS G489-V509Transmembrane domain: HMMER L401-L421, M483-V501, I526-I551 970356714CD1 550 S104 S106 S164 N310 N353 Transmembrane domain: HMMERS225 S279 S319 N39 N56 I148-Y165 S326 S332 S529 N99 Sugar (and other)transporter domain: HMMER_PFAM T224 T428 T523 T103-L527 T65 107611491CD1 559 S105 S110 S120 N339 N472 Transmembrane domains: HMMERS129 S347 S376 N490 A156-Y178; V203-F221; L239-Y262; S47 S524 S91A261-F280; F305-L324; P380-N400 T114 T192 T428 PROTEIN OLFACTORY CHANNELB0212.5 BLAST_PRODOM T68 T83 Y99 T09A12.3 T10B10.7 VANILLOID RECEPTORSUBTYPE F28H7.10 PD011151: N54-P186 VANILLOID RECEPTOR SUBTYPE 1PD137334: BLAST_PRODOM L440-P515 11 171968CD1 181 S142 S159 T113 N22Mitochondrial carrier proteins domains: HMMER_PFAM T64 C9-E79; Y85-W180Mitochondrial energy transfer proteins PROFILESCAN signature: A95-E146PROTEIN TRANSPORT TRANSMEMBRANE BLAST_PRODOM REPEAT MITOCHONDRIONCARRIER MEMBRANE INNER MITOCHONDRIAL ADP/ATP PD000117: P12-W179MITOCHONDRIAL ENERGY TRANSFER BLAST_DOMO PROTEINSDM00026|P38087|243-325: G101-W179 Mitochondrial carrier proteins motif:MOTIFS P12-L20; P114-M122 12 257274CD1 124 S27 T110 N33 Signal peptide:SPSCAN, HMMER M1-G22 Neurotransmitter-gated ion-channel HMMER_PFAMdomain: K38-M80 NEUROTRANSMITTER-GATED ION-CHANNELS BLAST_DOMODM00560|S53532|15-474: R26-L84 13 6355991CD1 2009 S243 S248 S286 N211N284 Transmembrane domains: HMMER S482 S490 S493 N295 N301 I122-M147;S213-I230; V250-L268; S510 S523 S528 N306 N338 Y399-V422; V761-N781;G803-A821; S53 S550 S558 N601 N621 W832-V852; L893-L911; V971-L991; S565S570 S576 N681 N892 M1251-Y1274; V1350-F1369; S586 S596 S603 N1064M1459-I1482; F1543-T1562; S607 S620 S628 N1080 I1576-S1594; I1602-F1620;S643 S694 S695 N1146 T1633-I1650; I1673-F1692; S708 S843 S860 N1378G1762-I1785 S915 S1060 S1090 N1392 Ion transport protein domains:HMMER_PFAM S1122 S1134 N1403 I124-V422; V764-L991; S1136 S1150 N1788I1214-I1482; F1537-I1785 S1155 S1328 IQ calmodulin-binding motif:HMMER_PFAM S1801 S1968 E1916-K1936 S1314 S1516 Sodium channel signaturePR00170: A107-; BLIMPS_PRINTS S1594 S1751 T217 C136 T308 T363 T391S213-G238; Q242-F269; D332-G355; T433 T465 T597 Y399-E428; V765-T793;G884-F912 T625 T683 T685 CHANNEL SODIUM IONIC VOLTAGEGATED BLAST_PRODOMT723 T955 T1003 PROTEIN TRANSMEMBRANE ION TRANSPORT T1250 T1247GLYCOPROTEIN DUPLICATION PD007385: T1317 T1380 K495-S620 T1405 T1430SODIUM CHANNEL PROTEIN BLAST_DOMO T1872 T1909 DM01376|P04774|884-1123:T1934 T1970 Y549 G884-F1124 Y1102 Y1439 ATP/GTP binding site (P-loop):G908-S915 MOTIFS Y1458 14 70035348CD1 538 S169 S220 S256 N371 N383Transmembrane domains: HMMER S264 S385 S443 N396 N401 V83-I101;C115-I134; T131-V153; S495 S535 S75 Y198-F216; T345-V364 T18 T246 T403Sugar (and other) transporter domain: HMMER_PFAM T520 S43-V484 Sugartransport proteins signature BLIMPS_BLOCKS BL00216: G51-S62; L133-A182Sugar transport proteins signature: PROFILESCAN L119-I184 SUGARTRANSPORT PROTEINS BLAST_DOMO DM00135|P09830|101-452: L119-G362;V426-I487 Sugar transporter motif: MOTIFS G97-S113 15 7472539CD1 742S139 S157 S22 N324 Transmembrane domains: HMMER S26 S380 S494 N329 N476I121-I140; I223-I240; L261-M280; S634 S643 S648 N664 L446-A466;V505-I521; L604-T622 S699 S712 T495 Sodium: solute symporter familydomain: HMMER_PFAM T52 T558 T711 I140-G569 Y583 Sodium: solute symportersignature BLIMPS_BLOCKS BL00456: A193-R222; L255-G309; P542-A551 Sodium:solute symporter family PROFILESCAN signatures: Q252-V299; D531-D592TRANSMEMBRANE TRANSPORT PERMEASE BLAST_PRODOM PROTEIN SODIUM SYMPORTPROLINE COTRANSPORTER SYMPORTER GLYCOPROTEIN PD000991: V197-G569 SODIUM:SOLUTE SYMPORTER FAMILY BLAST_DOMO DM00745|S59637|24-561: H117-T625Sodium solute symporter motif: MOTIFS G256-A281 16 817477CD1 426 S134S138 S193 N369 Transmembrane domains: HMMER S74 T335 V82-S109; I338-G356Monocarboxylate transporter domain: HMMER_PFAM A20-D426 do PEST;TRANSPORTER; LINKED; BLAST_DOMO DM05037|P53988|1-465: P7-P191; S209-L38917 1442166CD1 1197 S205 S224 S306 N150 N287 Transmembrane domains: HMMERS328 S612 S634 N420 N502 V67-W87; F445-I464 S712 S740 S776 N738 N1100E1-E2 ATPase domains: HMMER_PFAM S799 S851 S929 Q302-H393; A524-D599;E677-A880 S1127 S1152 T438 E1-E2 ATPases phosphorylation siteBLIMPS_BLOCKS T567 T596 T603 proteins signature BL00154: T66 T910 T913V489-G525; V527-V545; C723-F763; T961 T1190 T859-L882 P-typecation-transporting ATPase BLIMPS_PRINTS superfamily signature PR00119:D348-E362; C531-V545; A739-D749; C862-L881 PROBABLE CALCIUMTRANSPORTINGATPASE BLAST_PRODOM HYDROLASE CALCIUM TRANSPORT TRANSMEMBRANEPHOSPHORYLATION MAGNESIUM ATPBINDING PD023991: D943-G1189 E1-E2 ATPASESPHOSPHORYLATION SITE BLAST_DOMO DM00115|P54678|80-795: W263-G815;E806-L881 E1-E2 ATPase motif: MOTIFS D533-T539 18 2311751CD1 1771 S219S275 S294 N744 N832 Transmembrane domains: HMMER S306 S449 S454 N885N893 V119-L138; L228-T246; V1128- S468 S583 S658 N948 N1013 F1148;M1180-F1197; V1235-L1261 S667 S674 S716 N1111 ABC transporter domain:HMMER_PFAM S746 S762 S790 N1390 N353-G533; G1416-G1597 S813 S895 S939ABC transporters family signature: PROFILESCAN S1531 S1701 D440-D490;V1502-D1553 S1317 S1494 ATPBINDING TRANSPORTER CASSETTE ABC BLAST_PRODOMS1580 S1627 TRANSPORT PROTEIN GLYCOPROTEIN S1668 S1755 TRANSMEMBRANE RIMABCR PD005939: S1022 S1154 L1122-Y1306 S1359 S1371 ABC TRANSPORTERSFAMILY BLAST_DOMO S1397 T179 T290 DM00008|P41233|839-1045: V326-H532;T31 T393 T416 V1386-M1594 T547 T606 T648 ABC transporter motif: MOTIFST649 T867 T1437 L459-F473 T1443 T1479 ATP/GTP binding site (P-loop)MOTIFS T1550 T1687 G360-T367; G1423-T1430 T1748 T1432 T1570 T1619 Y72519 7472537CD1 474 S22 S232 S236 N296 N56 Transmembrane domains: HMMERS287 S436 T163 G77-V96; I175-T198; V342-F359; T400 T433 W377-L397;I396-I419; L443-I462 Transmembrane amino acid transporter HMMER_PFAMprotein domain: A72-M453 ACID AMINO PROTEIN TRANSPORTER BLAST_PRODOMPERMEASE TRANSMEMBRANE INTERGENIC REGION PUTATIVE PROLINE PD001875:S53-V361 TRANSPORTER PROTEIN PD138374: BLAST_PRODOM H327-W464 207472546CD1 752 S139 S22 S26 N196 N334 Transmembrane domains: HMMER S390S504 S644 N339 N486 I121-I140; S173-W195; I233-I250; S653 S658 S709 N674L271-M290; L456-A476; V515-I531; S722 T505 T52 L614-T632 T568 T721 Y593Sodium: solute symporter family domain: HMMER_PFAM Y150-G579 Sodium:solute symporter signature BLIMPS_BLOCKS BL00456: Y127-G181 A203-R232L265-G319 P552-A561 Sodium: solute symporter family PROFILESCANsignatures: Q262-V309; D541-D602 TRANSMEMBRANE TRANSPORT PERMEASEBLAST_PRODOM PROTEIN SODIUM SYMPORT PROLINE COTRANSPORTER SYMPORTERGLYCOPROTEIN PD000991: Y150-G579 SODIUM: SOLUTE SYMPORTER FAMILYBLAST_DOMO DM00745|S59637|24-561: H117-T635 Sodium solute symportersmotif: MOTIFS G266-A291 21 7474202CD1 654 S200 S226 S238 N161 N332Transmembrane domains: HMMER S284 S321 S328 N520 N646 D49-G72; F364-I382S486 S636 T155 Voltage gated chloride channels domain: HMMER_PFAM T17T280 T290 M67-Q484 T530 T540 T626 CBS domains: HMMER_PFAM Y51 H517-Q572;C593-S645 Chloride channel signature PR00762: BLIMPS_PRINTS P84-V101;V117-P136; A174-E193; M389-G409; G432-H448; T449-P468; F487-P501 PROTEINCHANNEL CHLORIDE BLAST_PRODOM TRANSMEMBRANE VOLTAGEGATED IONIC IONTRANSPORT CBS DOMAIN PD001036: Q80-L474 do CHANNEL; CHLORIDE; CLC-1;CLC-KA; BLAST_DOMO DM01220|P51800|52-686: F52-R76; G77-K654 227476280CD1 886 S136 S17 S280 N265 N582 Transmembrane domains: HMMER S341S40 S414 N7 K343-W362; S386-L405; M546-Y571; S580 S599 S678 I619-T637S729 S86 S880 Transient receptor potential signature BLIMPS_PRINTS T282T364 T407 PR01097: T491 T702 T745 G618-S639; F640-F653; T668-A681 T753T782 T788 CHANNEL PROTEIN CALCIUM ENTRY BLAST_PRODOM T882 CAPACITATIVEIONIC TRANSMEMBRANE ION TRANSPORT TRANSIENT PD004194: L23-H499 ANK MOTIFREPEAT DM03196|P48994|13-780: BLAST_DOMO D61-I567; E575-R688; E724-E75123 1713377CD1 512 S109 S132 S246 N257 Transmembrane domains: HMMER S304S330 S508 A49-I72; D307-L325; L451-Y470 T113 T234 Sugar transportproteins signature BLIMPS_BLOCKS BL00216: F139-G188 24 5842557CD1 475S115 S262 S284 N334 N341 Transmembrane domains: HMMER S389 S97 T462A12-Y35; Y155-L178; I194-L220; V226-Y246; A304-F324 Ion transportprotein domain: HMMER_PFAM L151-I416 25 7476643CD1 537 S193 S255 S298N504 N74 Signal peptide: SPSCAN S303 S445 S515 N90 M1-G66 T140 T403 T506Transmembrane domains: HMMER V112-V128; I385-L404; L414-I436; Y479-F497Sugar (and other) transporter domain: HMMER_PFAM A59-F514 Sugartransport proteins signatures: PROFILESCAN A152-L218 Glucose transportersignature PR00172: BLIMPS_PRINTS V317-Y338; I385-Q405; I416-G439A449-L467 Y479-L499 Sugar transporter signature PR00171: BLIMPS_PRINTSS68-V78; I168-M187; Y327-F337; I416-L437; G439-F451 SUGAR TRANSPORTPROTEINS BLAST_DOMO DM00135|P22732|132-466: R171-T506 Sugar transporter1 motif: MOTIFS S371-G386 Sugar transporter 2 motif: MOTIFS I173-R198 267611651CD1 905 S105 S140 S145 N218 N457 Transmembrane domains: HMMERS200 S26 S283 N689 L300-N318; S394-A412 S288 S435 S55 Transmembraneregion cyclic nucleotide HMMER_PFAM S617 S653 S671 gated channel: S698S721 S735 Y341-I527 S811 S819 S826 Cyclic nucleotide-binding domain:HMMER_PFAM S844 S876 T13 V555-A646 T170 T202 T220 POTASSIUM CHANNELIONIC CHANNEL BLAST_PRODOM T301 T326 T363 PD118772: T377 T433 T469E649-S902 T625 CAMP RECEPTOR PROTEIN CYCLIC BLAST_DOMONUCLEOTIDE-BINDING DOMAIN DM01165|I38465|562-948: H413-I418; S420-F685do POTASSIUM; CHANNEL; KST1; AKT1; BLAST_DOMO DM02383|I38465|353-560:T201-A412 27 2522075CD1 686 S293 S322 S472 N487 PROTEIN CHANNEL IONICION TRANSPORT BLAST_PRODOM S601 S608 T489 VOLTAGEGATED P64 CHLORIDE T566T619 T83 INTRACELLULAR CHLORINE PD017366: Q449-M685

[0376] TABLE 4 Polynucleotide Incyte Sequence Selected SEQ ID NO:Polynucleotide ID Length Fragment(s) Sequence Fragments 5′ Position 3′Position 28 7475353CB1 2984 1-605, 70527391V1 612 1298 2964-298470159545V1 2032 2614 70484059V1 1879 2569 70528817V1 1290 1981 3394211F8(LUNGNOT28) 1 603 624415R6 (PGANNOT01) 2454 2984 4099055F8 (BRAITUT26)456 1097 70483730V1 1265 1882 29 3107278CB1 1846 1-170 7249756H2(PROSTMY01) 1682 1846 5426789F6 (THYMTUT03) 1262 1807 4893528F8(LIVRTUT12) 636 1171 1546941R6 (PROSTUT04) 333 1053 7272275H1(OVARDIJ01) 1029 1694 4742175F6 (THYMNOR02) 1 637 30 7473394CB1 14581-1458 GNN.g7160536_000034_002 1 1458 31 7473900CB1 1234 FL180719_000011 1234 32 7475045CB1 1255 1-342 GNN.g7523773_000025_002 169 12556910236R8 (PITUDIR01) 1 672 33 7475611CB1 957 1-957GNN.g7329616_000008_002 2 957 34 7475617CB1 2407 1359-1412, 6769264H1(BRAUNOR01) 1667 2100 684-958, GNN.g7362716_000001_002 689 938 2229-24076084383H1 (LUNLTUT11) 23 664 5890656F6 (LIVRNON08) 1003 1365 7695062H1(LNODTUE01) 1895 2407 6966295H1 (SKINDIA01) 1340 1895 g7457275 1 49260148652D2 799 1149 5998083F7 (BRAZDIT04) 399 904 35 7473314CB1 27671-113, 652-805, 7930723H1 (COLNDIS02) 2135 2745 2733-2767, 132920F1(BMARNOT02) 1722 2165 2166-2190 g2207207 2220 2767 1645009T6 (HEARFET01)1493 2155 1710065H1 (PROSNOT16) 2544 2752 1645009F6 (HEARFET01) 10161568 6767169J1 (BRAUNOR01) 73 774 6748695H1 (BRAXNOT03) 2409 27503556343H1 (LUNGNOT31) 760 1027 GNN.g7533975_000016_002 1 543 3670356714CB1 2182 894-1332 71753989V1 1678 2182 7164046F8 (PLACNOR01) 6081349 71759169V1 895 1595 71757516V1 1484 2171 5796984F8 (PLACFET04) 1737 37 7611491CB1 2811 826-1021, 8107975J1 (MIXDDIE02) 1231 19702762-2811, 55030237H1 660 1315 1-176, 71749736V1 2060 2624 1526-167271749946V1 2161 2811 55030269H1 520 1232 7088214R8 (BRAUTDR03) 1 6067611491J1 (KIDCTME01) 1922 2605 70211216V1 1534 2030 38 171968CB1 20741-773, 71152449V1 1326 2016 1141-2074 7708502J1 (PANCNOE02) 351 100771302454V1 1370 2019 7722139J2 (THYRDIE01) 1 731 71153625V1 1420 20746777664J1 (OVARDIR01) 773 1375 39 257274CB1 1340 392-1340 257274R6(HNT2RAT01) 1 571 257274T6 (HNT2RAT01) 715 1340 40 6355991CB1 60271-558, 846-1005, 768641R6 (LUNGNOT04) 1243 1581 3413-4373, 5496021F9(BRABDIR01) 5626 6027 1239-3076 6355991F8 (LUNGDIS03) 5175 58165499076F6 (BRABDIR01) 5016 5432 GBI: g7381772_edit1 1 1377 GBI:g7381772_edit2 1378 6027 41 70035348CB1 2168 1-124, 7228345H1(BRAXTDR15) 1 512 1576-2168, 7664878J1 (UTRSTME01) 382 1063 184-2404822576H1 (PROSTUT17) 1888 2168 70037119V1 1383 1983 7664878H1(UTRSTME01) 945 1443 42 7472539CB1 2229 1755-2027, GNN.g6010343_006.edit1 2229 569-722, 130-409, 1320-1608 43 817477CB1 1520 1-151 7765238J1(URETTUE01) 921 1520 FL817477H1_00001 208 1432 7618286H1 (KIDNTUE01) 1573 44 1442166CB1 3950 1-1422, 6765069J1 (BRAUNOR01) 501 1204 3633-39507469439H1 (LUNGNOE02) 140 548 71374152V1 1962 2602 7651070J1 (STOMTDE01)751 1354 6332268H1 (BRANDIN01) 3413 3950 7176036H1 (BRSTTMC01) 1333 18917458415H1 (LIVRTUE01) 1379 2059 6836155H1 (BRSTNON02) 2107 27181208437R1 (BRSTNOT02) 2746 3321 71374816V1 2681 3277 5884688F8(LIVRNON08) 3252 3948 GBI.g7458720_edit 1 232 45 2311751CB1 5540 1-27446762808J1 (BRAUNOR01) 779 1317 71066032V1 642 1303 6911060J1 (PITUDIR01)1219 1795 5098681F8 (EPIMNON05) 5001 5540 6766537J1 (BRAUNOR01) 1 7474309533H1 (BRAUNOT01) 3898 4261 7179893H1 (BRAXDIC01) 4839 53486908865J1 (PITUDIR01) 2543 3171 6769078J1 (BRAUNOR01) 3679 42166770451H1 (BRAUNOR01) 4237 4919 7467144H1 (LUNGNOE02) 1336 18446765621H1 (BRAUNOR01) 1773 2436 6763740H1 (BRAUNOR01) 1831 24986893778J1 (BRAITDR03) 3173 3830 6889776H1 (BRAITDR03) 4380 49486953905H1 (BRAITDR02) 3099 3798 6977243H1 (BRAHTDR04) 2438 3070 467472537CB1 2074 1052-1392, 7984065H1 (UTRSTMC01) 1 541 1-462 g20192661752 2074 FL7472537_g5815493_g7406950 428 1852 47 7472546CB1 22591350-1638, 71400292V1 262 928 596-752, 71382167V1 1141 1592 130-409,7218664H1 (COLNTMC01) 1537 1905 1785-2057 GNN.g6114738_006 1 22594179344F6 (SINITUT03) 261 797 4669722H1 (SINTNOT24) 2014 2259 487474202CB1 2439 459-822 70218680V2 1909 2439 70218626V2 1435 214870219176V1 628 1127 7177066H1 (BRSTTMC01) 1596 2259 70219021V1 542 10037083037H1 (STOMTMR02) 1 619 70219400V1 1134 1609 70219013V1 953 1412 497476280CB1 2762 1862-1985, 2756231R6 (THP1AZS08) 1739 2271 1646-1738,2756231T6 (THP1AZS08) 2242 2736 1-1359, g1014431 1386 1648 2113-2184g3230934 2349 2762 GBI.g7622477_edit 1 2762 50 1713377CB1 1897 1-295,70587572V1 1077 1631 1041-1158 71875033V1 1459 1897 1527853T6(UCMCL5T01) 1343 1854 71413245V1 1 560 70587476V1 547 1287 71413060V1520 1185 51 5842557CB1 2361 1-688, 71052406V1 1311 1916 2076-2361,70794204V1 377 936 807-885 71412362V1 698 1312 7695065J1 (LNODTUE01) 1662 70730136V1 1820 2361 70795377V1 1277 1865 52 7476643CB1 2032 1-205,71207116V1 342 1121 1657-2032 71197621V1 1355 2032 71198062V1 1144 18334715941F6 (BRAIHCT01) 1 424 71205887V1 1093 1666 71204307V1 429 1135 537611651CB1 2779 2195-2779, 71047239V1 1343 1971 881-936 4726692F6(COLCTUT02) 913 1352 71047331V1 2011 2614 55049229H1 1 817 71047776V12202 2779 71046696V1 1931 2570 71048829V1 1331 1678 55049237J1 212 111854 2522075CB1 2430 1-837, FL2522075_g7717334_g7592636 1 2061 2144-24307079667H2 (STOMTMR02) 1765 2430

[0377] TABLE 5 Polynucleotide Incyte SEQ ID NO: Project IDRepresentative Library 28 7475353CB1 PROSNOT14 29 3107278CB1 BRAITUT0732 7475045CB1 SINITMC01 34 7475617CB1 LIVRNON08 35 7473314CB1 SKINBIT0136 70356714CB1 PLACNOR01 37 7611491CB1 KIDCTME01 38 171968CB1 BLADNOR0139 257274CB1 HNT2RAT01 40 6355991CB1 BRABDIR01 41 70035348CB1 LUNGNON0342 7472539CB1 SINTFEE02 43 817477CB1 KIDNTUE01 44 1442166CB1 BRSTNOT0245 2311751CB1 BRAUNOR01 46 7472537CB1 PANHTUR01 47 7472546CB1 SINITUT0348 7474202CB1 BRSTNOT33 49 7476280CB1 THP1AZS08 50 1713377CB1 BMARUNA0151 5842557CB1 SEMVNOT01 52 7476643CB1 LIVRNON08 53 7611651CB1 COLCTUT0254 2522075CB1 SPLNTUE01

[0378] TABLE 6 Library Vector Library Description BLADNOR01 PCDNA2.1This random primed library was constructed using RNA isolated from thebladder tissue of an 11-year-old Black male who died from a gunshotwound. Serology was positive for CMV. BMARUNA01 PSPORT1 Library wasconstructed using RNA isolated from CD34+ progenitor cells removed froma healthy Black male adult between age 18 and 45, during bilateral bonemarrow withdrawal from the posterior iliac crest of the pelvic bone. TheCD34+ progenitor cells were isolated from bone marrow mononuclear cellsusing positive immunomagnetic selection. The patient was a healthy bonemarrow donor. The patient was not taking any medications. BRABDIR01pINCY Library was constructed using RNA isolated from diseasedcerebellum tissue removed from the brain of a 57-year-old Caucasianmale, who died from a cerebrovascular accident. Patient history includedHuntington's disease, emphysema, and tobacco abuse. BRAITUT07 pINCYLibrary was constructed using RNA isolated from left frontal lobe tumortissue removed from the brain of a 32-year-old Caucasian male duringexcision of a cerebral meningeal lesion. Pathology indicated low gradedesmoplastic neuronal neoplasm, type not otherwise specified. The lesionformed a firm, circumscribed cyst-associated mass involving white matterand cortex. No definite glial component was evident to suggest adiagnosis of ganglioglioma. Family history included atheroscleroticcoronary artery disease. BRAUNOR01 pINCY This random primed library wasconstructed using RNA isolated from striatum, globus pallidus andposterior putamen tissue removed from an 81-year-old Caucasian femalewho died from a hemorrhage and ruptured thoracic aorta due toatherosclerosis. Pathology indicated moderate atherosclerosis involvingthe internal carotids, bilaterally; microscopic infarcts of the frontalcortex and hippocampus; and scattered diffuse amyloid plaques andneurofibrillary tangles, consistent with age. Grossly, the leptomeningesshowed only mild thickening and hyalinization along the superiorsagittal sinus. The remainder of the leptomeninges was thin andcontained some congested blood vessels. Mild atrophy was found mostly inthe frontal poles and lobes, and temporal lobes, bilaterally.Microscopically, there were pairs of Alzheimer type II astrocytes withinthe deep layers of the neocortex. There was increased satellitosisaround neurons in the deep gray matter in the middle frontal cortex. Theamygdala contained rare diffuse plaques and neurofibrillary tangles. Theposterior hippocampus contained a microscopic area of cystic cavitationwith hemosiderin-laden macrophages surrounded by reactive gliosis.Patient history included sepsis, cholangitis, post-operativeatelectasis, pneumonia CAD, cardiomegaly due to left ventricularhypertrophy, splenomegaly, arteriolonephrosclerosis, nodular colloidalgoiter, emphysema, CHF, hypothyroidism, and peripheral vascular disease.BRSTNOT02 PSPORT1 Library was constructed using RNA isolated fromdiseased breast tissue removed from a 55-year-old Caucasian femaleduring a unilateral extended simple mastectomy. Pathology indicatedproliferative fibrocysytic changes characterized by apocrine metaplasia,sclerosing adenosis, cyst formation, and ductal hyperplasia withoutatypia. Pathology for the associated tumor tissue indicated an invasivegrade 4 mammary adenocarcinoma. Patient history included atrialtachycardia and a benign neoplasm. Family history includedcardiovascular and cerebrovascular disease. BRSTNOT33 pINCY Library wasconstructed using RNA isolated from right breast tissue removed from a46-year-old Caucasian female during unilateral extended simplemastectomy with breast reconstruction. Pathology for the associatedtumor tissue indicated invasive grade 3 adenocarcinoma, ductal type,with apocrine features, nuclear grade 3 forming a mass in the outerquadrant. There was greater than 50% intraductal component. Patienthistory included breast cancer. COLCTUT02 pINCY Library was constructedusing RNA isolated from colon tumor tissue removed from the cecum of a30-year-old Caucasian female during partial colectomy, open liverbiopsy, incidental appendectomy, and permanent colostomy. Pathologyindicated carcinoid tumor (grade 1 neuroendocrine carcinoma) arising inthe terminal ileum, forming a mass in the right colon. Patient historyincluded chronic sinus infections and endometriosis. Family historyincluded hyperlipidemia, anxiety, upper lobe lung cancer, stomachcancer, liver cancer, and cirrhosis. HNT2RAT01 PBLUESCRIPT Library wasconstructed at Stratagene (STR937231), using RNA isolated from the hNT2cell line (derived from a human teratocarcinoma that exhibitedproperties characteristic of a committed neuronal precursor). Cells weretreated with retinoic acid for 24 hours KIDCTME01 PCDNA2.1 This 5'biased random primed library was constructed using RNA isolated fromkidney cortex tissue removed from a 65-year-old male duringnephroureterectomy. Pathology indicated the margins of resection werefree of involvement. Pathology for the matched tumor tissue indicatedgrade 3 renal cell carcinoma, clear cell type, forming a variegatedmulticystic mass situated within the mid-portion of the kidney. Thetumor invaded deeply into but not through the renal capsule. KIDNTUE01PCDNA2.1 This 5' biased random primed library was constructed using RNAisolated from kidney tumor tissue removed from a 46-year-old Caucasianmale during nephroureterectomy. Pathology indicated grade 2 renal cellcarcinoma, clear-cell type, forming a mass in the upper pole. Thepatient presented with kidney cancer, backache, headache, malignanthypertension, nausea, and vomiting. Previous surgeries included repairof indirect inguinal hernia. Patient medications included Lasix,Inderal, and Procardia. Family history included cerebrovascular accidentin the mother; acute myocardial infarction and atherosclerotic coronaryartery disease in the father; and type II diabetes in the sibling(s).LIVRNON08 pINCY This normalized library was constructed from 5.7 millionindependent clones from a pooled liver tissue library. Starting RNA wasmade from pooled liver tissue removed from a 4-year-old Hispanic malewho died from anoxia and a 16 week female fetus who died after 16-weeksgestation from anencephaly. Serologies were positive forcytolomegalovirus in the 4-year-old. Patient history included asthma inthe 4- year-old. Family history included taking daily prenatal vitaminsand mitral valve prolapse in the mother of the fetus. The library wasnormalized in 2 rounds using conditions adapted from Soares et al., PNAS(1994) 91: 9228 and Bonaldo et al., Genome Research 6 (1996): 791,except that a significantly longer (48 hours/round) reannealinghybridization was used. LIVRNON08 pINCY This normalized library wasconstructed from 5.7 million independent clones from a pooled livertissue library. Starting RNA was made from pooled liver tissue removedfrom a 4-year-old Hispanic male who died from anoxia and a 16 weekfemale fetus who died after 16-weeks gestation from anencephaly.Serologies were positive for cytolomegalovirus in the 4-year-old.Patient history included asthma in the 4- year-old. Family historyincluded taking daily prenatal vitamins and mitral valve prolapse in themother of the fetus. The library was normalized in 2 rounds usingconditions adapted from Soares et al., PNAS (1994) 91: 9228 and Bonaldoet al., Genome Research 6 (1996): 791, except that a significantlylonger (48 hours/round) reannealing hybridization was used. LUNGNON03PSPORT1 This normalized library was constructed from 2.56 millionindependent clones from a lung tissue library. RNA was made from lungtissue removed from the left lobe a 58-year-old Caucasian male during asegmental lung resection. Pathology for the associated tumor tissueindicated a metastatic grade 3 (of 4) osteosarcoma. Patient historyincluded soft tissue cancer, secondary cancer of the lung, prostatecancer, and an acute duodenal ulcer with hemorrhage. Patient alsoreceived radiation therapy to the retroperitoneum. Family historyincluded prostate cancer, breast cancer, and acute leukemia. Thenormalization and hybridization conditions were adapted from Soares etal., PNAS (1994) 91: 9228; Swaroop et al., NAR (1991) 19: 1954; andBonaldo et al., Genome Research (1996) 6: 791. PANHTUR01 PBK-CMV Thisrandom primed library was constructed RNA isolated from pancreatic tumortissue removed from a 65-year-old female. Pathology indicated well-differentiated neuroendocrine carcinoma (islet cell tumor), nucleargrade 1, forming a dominant mass in the distal pancreas. Multiplesmaller tumor nodules were immediately adjacent to the main mass. Theliver showed metastatic grade 1 islet cell tumor, forming multiplenodules. Multiple (4) pericholedochal lymph nodes contained metastaticgrade 1 islet cell tumor. PLACNOR01 PCDNA2.1 This random primed librarywas constructed using pooled cDNA from two different donors. cDNA wasgenerated using mRNA isolated from placental tissue removed from aCaucasian fetus (donor A), who died after 16 weeks' gestation from fetaldemise and hydrocephalus and from placental tissue removed from aCaucasian male fetus (donor B), who died after 18 weeks' gestation fromfetal demise. Patient history for donor A included umbilical cordwrapped around the head (3 times) and the shoulders (1 time). Serologywas positive for anti-CMV and remaining serologies were negative. Familyhistory included multiple pregnancies and live births, and an abortionin the mother. Serology was negative for donor B. PROSNOT14 pINCYLibrary was constructed using RNA isolated from diseased prostate tissueremoved from a 60-year-old Caucasian male during radical prostatectomyand regional lymph node excision. Pathology indicated adenofibromatoushyperplasia. Pathology for the associated tumor tissue indicated anadenocarcinoma (Gleason grade 3 + 4). The patient presented withelevated prostate specific antigen (PSA). Patient history included akidney cyst and hematuria. Family history included benign hypertension,cerebrovascular disease, and arteriosclerotic coronary artery disease.SEMVNOT01 pINCY Library was constructed using RNA isolated from seminalvesicle tissue removed from a 58-year-old Caucasian male during radicalprostatectomy. Pathology for the associated tumor tissue indicatedadenocarcinoma (Gleason grade 3 + 2) of the prostate. Adenofibromatoushyperplasia was also present. The patient presented with elevatedprostate specific antigen (PSA). Family history included a malignantbreast neoplasm. SINITMC01 pINCY This large size-fractionated librarywas constructed using pooled cDNA from two donors. cDNA was generatedusing mRNA isolated from ileum tissue removed from a 30-year-oldCaucasian female (donor A) during partial colectomy, open liver biopsy,and permanent colostomy, and from ileum tissue removed from a70-year-old Caucasian female (donor B) during right hemicolectomy, openliver biopsy, sigmoidoscopy, colonoscopy, and permanent colostomy.Pathology for the matched tumor tissue (donor A) indicated carcinoidtumor (grade 1 neuroendocrine carcinoma) arising in the terminal ileum.The tumor permeated through the ileal wall into the mesenteric fat andextended into the adherent cecum, where tumor extended through the bowelwall up to the mucosal surface. Multiple lymph nodes were positive fortumor. Additional (2) lymph nodes were also involved by direct tumorextension. Pathology for donor B indicated a non-tumorous margin ofileum. Pathology for the matched tumor (donor B) indicated invasivegrade 2 adenocarcinoma forming an ulcerated mass, situated distal to theileocecal valve. The tumor invaded through the muscularis propria justinto the serosal adipose tissue. One regional lymph node was positivefor a microfocus of metastatic adenocarcinoma. Donor A presented withflushing and unspecified abdominal/pelvic symptoms. Patient historyincluded endometriosis, and tobacco and alcohol abuse. Donor B's historyincluded a malignant breast neoplasm, type II diabetes, hyperlipidemia,viral hepatitis, an unspecified thyroid disorder, osteoarthritis, and amalignant skin neoplasm. Donor B's medication included tamoxifen.SINITUT03 pINCY Library was constructed using RNA isolated from ilealtumor tissue obtained from a 49-year-old Caucasian female duringdestruction of peritoneal tissue, peritoneal adhesiolysis, ileumresection, and permanent colostomy. Pathology indicated grade 4adenocarcinoma. Patient history included benign hypertension. Previoussurgeries included total abdominal hysterectomy, bilateralsalpingo-oophorectomy, regional lymph node excision, an incidentalappendectomy, and dilation and curettage. Family history included benignhypertension, cerebrovascular disease, hyperlipidemia, atheroscleroticcoronary artery disease, hyperlipidemia, type II diabetes, and stomachcancer. SINTFEE02 PCDNA2.1 This 5' biased random primed library wasconstructed using RNA isolated from small intestine tissue removed froma Caucasian male fetus who died from Patau's syndrome (trisomy 13) at20-weeks' gestation. Serology was negative. SKINBIT01 pINCY Library wasconstructed using RNA isolated from diseased skin tissue of the leftlower leg. Patient history included erythema nodosum of the left lowerleg. SPLNTUE01 PCDNA2.1 This 5' biased random primed library wasconstructed using RNA isolated from spleen tumor tissue removed from a28-year-old male during total splenectomy. Pathology indicated malignantlymphoma, diffuse large cell type, B-cell phenotype with abundantreactive T-cells and marked granulomatous response involving the spleen,where it formed approximately 45 nodules, liver, and multiple lymphnodes. THP1AZS08 PSPORT1 This subtracted THP-1 promonocyte cell linelibrary was constructed using 5.76 × 1e6 clones from a5-aza-2'-deoxycytidine (AZ) treated THP-1 cell library. Starting RNA wasmade from THP-1 promonocyte cells treated for three days with 0.8micromolar AZ. The donor had acute monocytic leukemia The hybridizationprobe for subtraction was derived from a similarly constructed library,made from 1 microgram of polyA RNA isolated from untreated THP-1 cells.5.76 million clones from the AZ-treated THP-1 cell library were thensubjected to two rounds of subtractive hybridization with 5 millionclones from the untreated THP-1 cell library. Subtractive hybridizationconditions were based on the methodologies of Swaroop et al., NAR (1991)19: 1954, and Bonaldo et al., Genome Research (1996) 6: 791.

[0379] TABLE 7 Program Description Reference Parameter Threshold ABI Aprogram that removes vector sequences and Applied Biosystems, FosterCity, CA. FACTURA masks ambiguous bases in nucleic acid sequences. ABI/A Fast Data Finder useful in comparing and Applied Biosystems, FosterCity, CA; Mismatch < 50% PARACEL annotating amino acid or nucleic acidsequences. Paracel Inc., Pasadena, CA. FDF ABI A program that assemblesnucleic acid sequences. Applied Biosystems, Foster City, CA.AutoAssembler BLAST A Basic Local Alignment Search Tool useful inAltschul, S. F. et al. (1990) J. Mol. Biol. ESTs: Probability value =sequence similarity search for amino acid and 215: 403-410; Altschul, S.F. et al. (1997) 1.0E−8 or less nucleic acid sequences. BLAST includesfive Nucleic Acids Res. 25: 3389-3402. Full Length sequences: functions:blastp, blastn, blastx, tblastn, and tblastx. Probability value =1.0E−10 or less FASTA A Pearson and Lipman algorithm that searches forPearson, W. R. and D. J. Lipman (1988) Proc. ESTs: fasta E value =similarity between a query Natl. Acad Sci. USA 1.06E−6 sequence and agroup of 85: 2444-2448; Pearson, Assembled ESTs: fasta sequences of thesame type. FASTA comprises as W. R. (1990) Methods Enzymol. 183: 63-98;Identity = 95% or greater and least five functions: fasta, tfasta,fastx, tfastx, and and Smith, T. F. and M. S. Waterman (1981) Matchlength = 200 bases or ssearch. Adv. Appl. Math. 2: 482-489. greater;fastx E value = 1.0E−8 or less Full Length sequences: fastx score = 100or greater BLIMPS A BLocks IMProved Searcher that matches a Henikoff, S.and J. G. Henikoff (1991) Nucleic Probability value = 1.0E−3 sequenceagainst those in BLOCKS, PRINTS, Acids Res. 19: 6565-6572; Henikoff, J.G. and or less DOMO, PRODOM, and PFAM databases to search S. Henikoff(1996) Methods Enzymol. for gene families, sequence homology, and 266:88-105; and Attwood, T. K. et al. (1997) structural fingerprint regions.J. Chem. Inf. Comput. Sci. 37: 417-424. HMMER An algorithm for searchinga query sequence against Krogh, A. et al. (1994) J. Mol. Biol. PFAMhits: Probability value = hidden Markov model (HMM)-based databases of235: 1501-1531; Sonnhammer, E. L. L. et al. 1.0E−3 or less proteinfamily consensus sequences, such as PFAM. (1988) Nucleic Acids Res. 26:320-322; Signal peptide hits: Score = 0 or Durbin, R. et al. (1998) OurWorld View, in a greater Nutshell, Cambridge Univ. Press, pp. 1-350.ProfileScan An algorithm that searches for structural and Gribskov, M.et al. (1988) CABIOS 4: 61-66; Normalized quality score ≧ sequencemotifs in protein sequences that match Gribskov, M. et al. (1989)Methods Enzymol. GCG-specified “HIGH” sequence patterns defined inProsite. 183: 146-159; Bairoch, A. et al. (1997) value for thatparticular Prosite Nucleic Acids Res. 25: 217-221. motif. Generally,score = 1.4-2.1. Phred A base-calling algorithm that examines automatedEwing, B. et al. (1998) Genome Res. sequencer traces with high 8:175-185; Ewing, B. and P. Green sensitivity and probability. (1998)Genome Res. 8: 186-194. Phrap A Phils Revised Assembly Program includingSmith, T. F. and M. S. Waterman (1981) Adv. Score = 120 or greater; SWATand CrossMatch, programs based on Appl. Math. 2: 482-489; Smith, Matchlength = 56 or greater efficient implementation of the Smith-Waterman T.F. and M. S. Waterman (1981) J. Mol. algorithm, useful in searchingsequence Biol. 147: 195-197; and Green, P., homology and assembling DNAsequences. University of Washington, Seattle, WA. Consed A graphicaltool for viewing and editing Phrap Gordon, D. et al. (1998) assemblies.Genome Res. 8: 195-202. SPScan A weight matrix analysis program thatscans protein Nielson, H. et al. (1997) Protein Engineering Score = 3.5or greater sequences for the presence of 10: 1-6; Claverie, J. M. and S.Audic (1997) secretory signal peptides. CABIOS 12: 431-439. TMAP Aprogram that uses weight matrices to delineate Persson, B. and P. Argos(1994) J. Mol. Biol. transmembrane segments on protein sequences and237: 182-192; Persson, B. and P. Argos (1996) determine orientation.Protein Sci. 5: 363-371. TMHMMER A program that uses a hidden Markovmodel Sonnhammer, E. L. et al. (1998) (HMM) to delineate Proc. SixthIntl. Conf. on Intelligent Systems transmembrane segments on for Mol.Biol., Glasgow et al., eds., protein sequences and determineorientation. The Am. Assoc. for Artificial Intelligence Press, MenloPark, CA, pp. 175-182. Motifs A program that searches amino acidsequences for Bairoch, A. et al. (1997) Nucleic Acids patterns thatmatched those defined in Prosite. Res. 25: 217-221; Wisconsin PackageProgram Manual, version 9, page M51-59, Genetics Computer Group,Madison, WI.

[0380]

1 54 1 842 PRT Homo sapiens misc_feature Incyte ID No 7475353CD1 1 MetVal Thr Val Gly Asn Tyr Cys Glu Ala Glu Gly Pro Val Gly 1 5 10 15 ProAla Trp Met Gln Asp Gly Leu Ser Pro Cys Phe Phe Phe Thr 20 25 30 Leu ValPro Ser Thr Arg Met Ala Leu Gly Thr Leu Ala Leu Val 35 40 45 Leu Ala LeuPro Cys Arg Arg Arg Glu Arg Pro Ala Gly Ala Asp 50 55 60 Ser Leu Ser TrpGly Ala Gly Pro Arg Ile Ser Pro Tyr Val Leu 65 70 75 Gln Leu Leu Leu AlaThr Leu Gln Ala Ala Leu Pro Leu Ala Gly 80 85 90 Leu Ala Gly Arg Val GlyThr Ala Arg Gly Ala Pro Leu Pro Ser 95 100 105 Tyr Leu Leu Leu Ala SerVal Leu Glu Ser Leu Ala Gly Ala Cys 110 115 120 Gly Leu Trp Leu Leu ValVal Glu Arg Ser Gln Ala Arg Gln Arg 125 130 135 Leu Ala Met Gly Ile TrpIle Lys Phe Arg His Ser Pro Gly Leu 140 145 150 Leu Leu Leu Trp Thr ValAla Phe Ala Ala Glu Asn Leu Ala Leu 155 160 165 Val Ser Trp Asn Ser ProGln Trp Trp Trp Ala Arg Ala Asp Leu 170 175 180 Gly Gln Gln Val Gln PheSer Leu Trp Val Leu Arg Tyr Val Val 185 190 195 Ser Gly Gly Leu Phe ValLeu Gly Leu Trp Ala Pro Gly Leu Arg 200 205 210 Pro Gln Ser Tyr Thr LeuGln Val His Glu Glu Asp Gln Asp Val 215 220 225 Glu Arg Ser Gln Val ArgSer Ala Ala Gln Gln Ser Thr Trp Arg 230 235 240 Asp Phe Gly Arg Lys LeuArg Leu Leu Ser Gly Tyr Leu Trp Pro 245 250 255 Arg Gly Ser Pro Ala LeuGln Leu Val Val Leu Ile Cys Leu Gly 260 265 270 Leu Met Gly Leu Glu ArgAla Leu Asn Val Leu Val Pro Ile Phe 275 280 285 Tyr Arg Asn Ile Val AsnLeu Leu Thr Glu Lys Ala Pro Trp Asn 290 295 300 Ser Leu Ala Trp Thr ValThr Ser Tyr Val Phe Leu Lys Phe Leu 305 310 315 Gln Gly Gly Gly Thr GlySer Thr Gly Phe Val Ser Asn Leu Arg 320 325 330 Thr Phe Leu Trp Ile ArgVal Gln Gln Phe Thr Ser Arg Arg Val 335 340 345 Glu Leu Leu Ile Phe SerHis Leu His Glu Leu Ser Leu Arg Trp 350 355 360 His Leu Gly Arg Arg ThrGly Glu Val Leu Arg Ile Ala Asp Arg 365 370 375 Gly Thr Ser Ser Val ThrGly Leu Leu Ser Tyr Leu Val Phe Asn 380 385 390 Val Ile Pro Thr Leu AlaAsp Ile Ile Ile Gly Ile Ile Tyr Phe 395 400 405 Ser Met Phe Phe Asn AlaTrp Phe Gly Leu Ile Val Phe Leu Cys 410 415 420 Met Ser Leu Tyr Leu ThrLeu Thr Ile Val Val Thr Glu Trp Arg 425 430 435 Thr Lys Phe Arg Arg AlaMet Asn Thr Gln Glu Asn Ala Thr Arg 440 445 450 Ala Arg Ala Val Asp SerLeu Leu Asn Phe Glu Thr Val Lys Tyr 455 460 465 Tyr Asn Ala Glu Ser TyrGlu Val Glu Arg Tyr Arg Glu Ala Ile 470 475 480 Ile Lys Tyr Gln Gly LeuGlu Trp Lys Ser Ser Ala Ser Leu Val 485 490 495 Leu Leu Asn Gln Thr GlnAsn Leu Val Ile Gly Leu Gly Leu Leu 500 505 510 Ala Gly Ser Leu Leu CysAla Tyr Phe Val Thr Glu Gln Lys Leu 515 520 525 Gln Val Gly Asp Tyr ValLeu Phe Gly Thr Tyr Ile Ile Gln Leu 530 535 540 Tyr Met Pro Leu Asn TrpPhe Gly Thr Tyr Tyr Arg Met Ile Gln 545 550 555 Thr Asn Phe Ile Asp MetGlu Asn Met Phe Asp Leu Leu Lys Glu 560 565 570 Glu Thr Glu Val Lys AspLeu Pro Gly Ala Gly Pro Leu Arg Phe 575 580 585 Gln Lys Gly Arg Ile GluPhe Glu Asn Val His Phe Ser Tyr Ala 590 595 600 Asp Gly Arg Glu Thr LeuGln Asp Val Ser Phe Thr Val Met Pro 605 610 615 Gly Gln Thr Leu Ala LeuVal Gly Pro Ser Gly Ala Gly Lys Ser 620 625 630 Thr Ile Leu Arg Leu LeuPhe Arg Phe Tyr Asp Ile Ser Ser Gly 635 640 645 Cys Ile Arg Ile Asp GlyGln Asp Ile Ser Gln Val Thr Gln Ala 650 655 660 Ser Leu Arg Ser His IleGly Val Val Pro Gln Asp Thr Val Leu 665 670 675 Phe Asn Asp Thr Ile AlaAsp Asn Ile Arg Tyr Gly Arg Val Thr 680 685 690 Ala Gly Asn Asp Glu ValGlu Ala Ala Ala Gln Ala Ala Gly Ile 695 700 705 His Asp Ala Ile Met AlaPhe Pro Glu Gly Tyr Arg Thr Gln Val 710 715 720 Gly Glu Arg Gly Leu LysLeu Ser Gly Gly Glu Lys Gln Arg Val 725 730 735 Ala Ile Ala Arg Thr IleLeu Lys Ala Pro Gly Ile Ile Leu Leu 740 745 750 Asp Glu Ala Thr Ser AlaLeu Asp Thr Ser Asn Glu Arg Ala Ile 755 760 765 Gln Ala Ser Leu Ala LysVal Cys Ala Asn Arg Thr Thr Ile Val 770 775 780 Val Ala His Arg Leu SerThr Val Val Asn Ala Asp Gln Ile Leu 785 790 795 Val Ile Lys Asp Gly CysIle Val Glu Arg Gly Arg His Glu Ala 800 805 810 Leu Leu Ser Arg Gly GlyVal Tyr Ala Asp Met Trp Gln Leu Gln 815 820 825 Gln Gly Gln Glu Glu ThrSer Glu Asp Thr Lys Pro Gln Thr Met 830 835 840 Glu Arg 2 461 PRT Homosapiens misc_feature Incyte ID No 3107278CD1 2 Met Pro Gly Arg Ser IleSer Leu Ser Ser Pro Tyr Trp Trp Ile 1 5 10 15 Asn Leu Trp Tyr Leu IleThr Gly Cys Ile Ala Asp Trp Val Gly 20 25 30 Arg Arg Pro Val Leu Leu PheSer Ile Ile Phe Ile Leu Ile Phe 35 40 45 Gly Leu Thr Val Ala Leu Ser ValAsn Val Thr Met Phe Ser Thr 50 55 60 Leu Arg Phe Phe Glu Gly Phe Cys LeuAla Gly Ile Ile Leu Thr 65 70 75 Leu Tyr Ala Leu Arg Ile Glu Leu Cys ProPro Gly Lys Arg Phe 80 85 90 Met Ile Thr Met Val Ala Ser Phe Val Ala MetAla Gly Gln Phe 95 100 105 Leu Met Pro Gly Leu Ala Ala Leu Cys Arg AspTrp Gln Val Leu 110 115 120 Gln Ala Leu Ile Ile Cys Pro Phe Leu Leu MetLeu Leu Tyr Trp 125 130 135 Ser Ile Phe Pro Glu Ser Leu Arg Trp Leu MetAla Thr Gln Gln 140 145 150 Phe Glu Ser Ala Lys Arg Leu Ile Leu His PheThr Gln Lys Asn 155 160 165 Arg Met Asn Pro Glu Gly Asp Ile Lys Gly ValIle Pro Glu Leu 170 175 180 Glu Lys Glu Leu Ser Arg Arg Pro Lys Lys ValCys Ile Val Lys 185 190 195 Val Val Gly Thr Arg Asn Leu Trp Lys Asn IleVal Val Leu Cys 200 205 210 Val Asn Ser Leu Thr Gly Tyr Gly Ile His HisCys Phe Ala Arg 215 220 225 Ser Met Met Gly His Glu Val Lys Val Pro LeuLeu Glu Asn Phe 230 235 240 Tyr Ala Asp Tyr Tyr Thr Thr Ala Ser Ile AlaLeu Val Ser Cys 245 250 255 Leu Ala Met Cys Val Val Val Arg Phe Leu GlyArg Arg Gly Gly 260 265 270 Leu Leu Leu Phe Met Ile Leu Thr Ala Leu AlaSer Leu Leu Gln 275 280 285 Leu Gly Leu Leu Asn Leu Ile Gly Lys Tyr SerGln His Pro Asp 290 295 300 Ser Gly Met Ser Asp Ser Val Lys Asp Lys PheSer Ile Ala Phe 305 310 315 Ser Ile Val Gly Met Phe Ala Ser His Ala ValGly Ser Leu Ser 320 325 330 Val Phe Phe Cys Ala Glu Ile Thr Pro Thr ValIle Arg Cys Gly 335 340 345 Gly Leu Gly Leu Val Leu Ala Ser Ala Gly PheGly Met Leu Thr 350 355 360 Ala Pro Ile Ile Glu Leu His Asn Gln Lys GlyTyr Phe Leu His 365 370 375 His Ile Ile Phe Ala Cys Cys Thr Leu Ile CysIle Ile Cys Ile 380 385 390 Leu Leu Leu Pro Glu Ser Arg Asp Gln Asn LeuPro Glu Asn Ile 395 400 405 Ser Asn Gly Glu His Tyr Thr Arg Gln Pro LeuLeu Pro His Lys 410 415 420 Lys Gly Glu Gln Pro Leu Leu Leu Thr Asn AlaGlu Leu Lys Asp 425 430 435 Tyr Ser Gly Leu His Asp Ala Ala Ala Ala GlyAsp Thr Leu Pro 440 445 450 Glu Gly Ala Thr Ala Asn Gly Met Lys Ala Met455 460 3 485 PRT Homo sapiens misc_feature Incyte ID No 7473394CD1 3Met Gln Asn Ile Thr Lys Glu Phe Gly Thr Phe Lys Ala Asn Asp 1 5 10 15Asn Ile Asn Leu Gln Val Lys Ala Gly Glu Ile His Ala Leu Leu 20 25 30 GlyGlu Asn Gly Ala Gly Lys Ser Thr Leu Met Asn Val Leu Ser 35 40 45 Gly LeuLeu Glu Pro Thr Ser Gly Lys Ile Leu Met Arg Gly Lys 50 55 60 Glu Val GlnIle Thr Ser Pro Thr Lys Ala Asn Gln Leu Gly Ile 65 70 75 Gly Met Val HisGln His Phe Met Leu Val Asp Ala Phe Thr Val 80 85 90 Thr Glu Asn Ile ValLeu Gly Ser Glu Pro Ser Arg Ala Gly Met 95 100 105 Leu Asp His Lys LysAla Arg Lys Glu Ile Gln Lys Val Ser Glu 110 115 120 Gln Tyr Gly Leu SerVal Asn Pro Asp Ala Tyr Val Arg Asp Ile 125 130 135 Ser Val Gly Met GluGln Arg Val Glu Ile Leu Lys Thr Leu Tyr 140 145 150 Arg Gly Ala Asp ValLeu Ile Phe Asp Glu Pro Thr Ala Val Leu 155 160 165 Thr Pro Gln Glu IleAsp Glu Leu Ile Val Ile Met Lys Glu Leu 170 175 180 Val Lys Glu Gly LysSer Ile Ile Leu Ile Thr His Lys Leu Asp 185 190 195 Glu Ile Lys Ala ValAla Asp Arg Cys Thr Val Ile Arg Arg Gly 200 205 210 Lys Gly Ile Gly ThrVal Asn Val Lys Asp Val Thr Ser Gln Gln 215 220 225 Leu Ala Asp Met MetVal Gly Arg Ala Val Ser Phe Lys Thr Met 230 235 240 Lys Lys Glu Ala LysPro Gln Glu Val Val Leu Ser Ile Glu Asn 245 250 255 Leu Val Val Lys GluAsn Arg Gly Leu Glu Ala Val Lys Asn Leu 260 265 270 Asn Leu Glu Val ArgAla Gly Glu Val Leu Gly Ile Ala Gly Ile 275 280 285 Asp Gly Asn Gly GlnSer Glu Leu Ile Gln Ala Leu Thr Gly Leu 290 295 300 Arg Lys Ala Glu SerGly His Ile Lys Leu Lys Gly Glu Asp Ile 305 310 315 Thr Asn Lys Lys ProArg Lys Ile Thr Glu His Gly Val Gly His 320 325 330 Val Pro Glu Asp ArgHis Lys Tyr Gly Leu Val Leu Asp Met Thr 335 340 345 Leu Ser Glu Asn IleAla Leu Gln Thr Tyr His Gln Lys Pro Tyr 350 355 360 Ser Lys Asn Gly MetLeu Asn Tyr Ser Val Ile Asn Glu His Ala 365 370 375 Arg Glu Leu Ile GluGlu Tyr Asp Val Arg Thr Thr Asn Glu Leu 380 385 390 Val Pro Ala Lys AlaLeu Ser Gly Gly Asn Gln Gln Lys Ala Ile 395 400 405 Ile Ala Arg Ile ValAsp Arg Asp Pro Asp Leu Leu Ile Val Ala 410 415 420 Asn Pro Thr Arg GlyLeu Asp Val Gly Ala Ile Glu Phe Ile His 425 430 435 Lys Arg Leu Ile GluGln Arg Asp Lys Tyr Lys Ala Val Leu Leu 440 445 450 Ile Ser Phe Glu LeuGlu Glu Ile Leu Asn Val Ser Asp Arg Ile 455 460 465 Ala Val Ile His GluGly Glu Ile Val Gly Ile Val Asp Pro Lys 470 475 480 Glu Thr Ser Glu Asn485 4 301 PRT Homo sapiens misc_feature Incyte ID No 7473900CD1 4 MetLys Ser Gly Pro Gly Ile Gln Ala Ala Ile Asp Leu Thr Ala 1 5 10 15 GlyAla Ala Gly Gly Thr Ala Cys Val Leu Thr Gly Gln Pro Phe 20 25 30 Asp ThrIle Lys Val Lys Met Gln Thr Phe Pro Asp Leu Tyr Lys 35 40 45 Gly Leu ThrAsp Cys Phe Leu Lys Thr Tyr Ala Gln Val Gly Leu 50 55 60 Arg Gly Phe TyrLys Gly Thr Gly Pro Ala Leu Met Ala Tyr Val 65 70 75 Ala Glu Asn Ser ValLeu Phe Met Cys Tyr Gly Phe Cys Gln Gln 80 85 90 Phe Val Arg Lys Val AlaGly Met Asp Lys Gln Ala Lys Leu Ser 95 100 105 Asp Leu Gln Thr Ala AlaAla Gly Ser Phe Ala Ser Ala Phe Ala 110 115 120 Ala Leu Ala Leu Cys ProThr Glu Leu Val Lys Cys Arg Leu Gln 125 130 135 Thr Met Tyr Glu Met GluMet Ser Gly Lys Ile Ala Lys Ser His 140 145 150 Asn Thr Ile Trp Ser ValVal Lys Gly Ile Leu Lys Lys Asp Gly 155 160 165 Pro Leu Gly Phe Tyr HisGly Leu Ser Ser Thr Leu Leu Gln Glu 170 175 180 Val Pro Gly Tyr Phe PhePhe Phe Gly Gly Tyr Glu Leu Ser Arg 185 190 195 Ser Phe Phe Ala Ser GlyArg Ser Lys Asp Glu Leu Gly Pro Val 200 205 210 His Leu Met Leu Ser GlyGly Val Ala Gly Ile Cys Leu Trp Leu 215 220 225 Val Val Phe Pro Val AspCys Ile Lys Ser Arg Ile Gln Val Leu 230 235 240 Ser Met Tyr Gly Lys GlnAla Gly Phe Ile Gly Thr Leu Leu Ser 245 250 255 Val Val Arg Asn Glu GlyIle Val Ala Leu Tyr Ser Gly Leu Lys 260 265 270 Ala Thr Met Ile Arg AlaIle Pro Ala Asn Gly Ala Leu Phe Val 275 280 285 Ala Tyr Glu Tyr Ser ArgLys Met Met Met Lys Gln Leu Glu Ala 290 295 300 Tyr 5 304 PRT Homosapiens misc_feature Incyte ID No 7475045CD1 5 Met Glu Thr Val Pro ProAla Val Asp Leu Val Leu Gly Ala Ser 1 5 10 15 Ala Cys Cys Leu Ala CysVal Phe Thr Asn Pro Leu Glu Val Val 20 25 30 Lys Thr Arg Leu Gln Leu GlnGly Glu Leu Gln Ala Arg Gly Thr 35 40 45 Tyr Pro Arg Pro Tyr His Gly PheIle Ala Ser Val Ala Ala Val 50 55 60 Ala Arg Ala Asp Gly Leu Trp Gly LeuGln Lys Gly Leu Ala Ala 65 70 75 Gly Leu Leu Tyr Gln Gly Leu Met Asn GlyVal Arg Phe Tyr Cys 80 85 90 Tyr Ser Leu Ala Cys Gln Ala Gly Leu Thr GlnGln Pro Gly Gly 95 100 105 Thr Val Val Ala Gly Ala Val Ala Gly Ala LeuGly Ala Phe Val 110 115 120 Gly Ser Pro Ala Tyr Leu Ile Lys Thr Gln LeuGln Ala Gln Thr 125 130 135 Val Ala Ala Val Ala Val Gly His Gln His AsnHis Gln Thr Val 140 145 150 Leu Gly Ala Leu Glu Thr Ile Trp Arg Gln GlnGly Leu Leu Gly 155 160 165 Leu Trp Gln Gly Val Gly Gly Ala Val Pro ArgVal Met Val Gly 170 175 180 Ser Ala Ala Gln Leu Ala Thr Phe Ala Ser AlaLys Ala Trp Val 185 190 195 Gln Lys Gln Gln Trp Leu Pro Glu Asp Ser TrpLeu Val Ala Leu 200 205 210 Ala Gly Gly Met Ile Ser Ser Ile Ala Val ValVal Val Met Thr 215 220 225 Pro Phe Asp Val Val Ser Thr Arg Leu Tyr AsnGln Pro Val Asp 230 235 240 Thr Ala Gly Arg Gly Gln Leu Tyr Gly Gly LeuThr Asp Cys Met 245 250 255 Val Lys Ile Trp Arg Gln Glu Gly Pro Leu AlaLeu Tyr Lys Gly 260 265 270 Leu Gly Pro Ala Tyr Leu Arg Leu Gly Pro HisThr Ile Leu Ser 275 280 285 Met Leu Phe Trp Asp Glu Leu Arg Lys Leu AlaGly Arg Ala Gln 290 295 300 His Lys Gly Thr 6 278 PRT Homo sapiensmisc_feature Incyte ID No 7475611CD1 6 Met Ser Ala Lys Val Leu Leu SerThr Glu His Leu Tyr Ala Thr 1 5 10 15 His Pro Gly Arg Pro Met Val LeuThr Asp Val Asn Val Ser Phe 20 25 30 Arg Ala Gly Val Arg Val Ala Ile LeuGly Ala Asn Gly Ser Gly 35 40 45 Lys Thr Thr Leu Met Arg Cys Leu Ser GlySer Leu Lys Pro Ala 50 55 60 Lys Gly His Val Lys Arg Gly Asp Ile Val ValSer Tyr Gly Arg 65 70 75 Ala Gln Leu Arg Glu His Arg Arg Ala Val Gln LeuVal Leu Gln 80 85 90 Asp Pro Asp Asp Gln Leu Phe Ser Ala Asp Val Ser GlnAsp Val 95 100 105 Ser Phe Gly Pro Met Asn Met Gly Leu Lys Val Asp GluVal Arg 110 115 120 Asp Arg Val Ser Glu Ser Leu Glu Leu Leu Gly Ala SerHis Leu 125 130 135 Ala Glu Arg Ala Thr Tyr Gln Leu Ser Tyr Gly Glu ArgLys Arg 140 145 150 Val Ala Val Ala Gly Ala Val Ala Met Arg Pro Asp LeuLeu Leu 155 160 165 Leu Asp Glu Pro Thr Ala Gly Leu Asp Pro Val Gly ValThr Gln 170 175 180 Met Leu Glu Ala Leu Asp Arg Leu Arg Asp His Gly ThrThr Val 185 190 195 Ala Met Ala Thr His Asp Val Asp Leu Ala Leu Ala TrpAla Gln 200 205 210 Glu Ala Leu Val Val Val Asp Gly Gln Val His Gln GlyPro Ile 215 220 225 Gly Glu Leu Leu Ala Asp Ala Asp Thr Val Gly Arg AlaHis Leu 230 235 240 His Leu Pro Trp Pro Leu Glu Leu Ala Arg Arg Leu GlyVal Arg 245 250 255 Asp Leu Pro Arg Thr Met Asp Asp Val Val Ala Met LeuSer Asp 260 265 270 Asn Pro Ser Pro Ala Pro Ser Asn 275 7 673 PRT Homosapiens misc_feature Incyte ID No 7475617CD1 7 Met Glu Glu Leu Ala ThrGlu Lys Glu Ala Glu Glu Ser His Arg 1 5 10 15 Gln Asp Ser Val Ser LeuLeu Thr Phe Ile Leu Leu Leu Thr Leu 20 25 30 Thr Ile Leu Thr Ile Trp LeuPhe Lys His Arg Arg Val Arg Phe 35 40 45 Leu His Glu Thr Gly Leu Ala MetIle Tyr Gly Leu Ile Val Gly 50 55 60 Val Ile Leu Arg Tyr Gly Thr Pro AlaThr Ser Gly Arg Asp Lys 65 70 75 Ser Leu Ser Cys Thr Gln Glu Asp Arg AlaPhe Ser Thr Leu Leu 80 85 90 Val Asn Val Ser Gly Lys Phe Phe Glu Tyr ThrLeu Lys Gly Glu 95 100 105 Ile Ser Pro Gly Lys Ile Asn Ser Val Glu GlnAsn Asp Met Leu 110 115 120 Arg Lys Val Thr Phe Asp Pro Glu Val Phe PheAsn Ile Leu Leu 125 130 135 Pro Pro Ile Ile Phe His Ala Gly Tyr Ser LeuLys Lys Arg His 140 145 150 Phe Phe Arg Asn Leu Gly Ser Ile Leu Ala TyrAla Phe Leu Gly 155 160 165 Thr Ala Val Ser Cys Phe Ile Ile Gly Asn LeuMet Tyr Gly Val 170 175 180 Val Lys Leu Met Lys Ile Met Gly Gln Leu SerAsp Lys Phe Tyr 185 190 195 Tyr Thr Asp Cys Leu Phe Phe Gly Ala Ile IleSer Ala Thr Asp 200 205 210 Pro Val Thr Val Leu Ala Ile Phe Asn Glu LeuHis Ala Asp Val 215 220 225 Asp Leu Tyr Ala Leu Leu Phe Gly Glu Ser ValLeu Asn Asp Ala 230 235 240 Val Ala Ile Val Leu Ser Ser Ser Ile Val AlaTyr Gln Pro Ala 245 250 255 Gly Leu Asn Thr His Ala Phe Asp Ala Ala AlaPhe Phe Lys Ser 260 265 270 Val Gly Ile Phe Leu Gly Ile Phe Ser Gly SerPhe Thr Met Gly 275 280 285 Ala Val Thr Gly Val Val Thr Ala Leu Val ThrLys Phe Thr Lys 290 295 300 Leu His Cys Phe Pro Leu Leu Glu Thr Ala LeuPhe Phe Leu Met 305 310 315 Ser Trp Ser Thr Phe Leu Leu Ala Glu Ala CysGly Phe Thr Gly 320 325 330 Val Val Ala Val Leu Phe Cys Gly Ile Thr GlnAla His Tyr Thr 335 340 345 Tyr Asn Asn Leu Ser Val Glu Ser Arg Ser ArgThr Lys Gln Leu 350 355 360 Phe Glu Val Leu His Phe Leu Ala Glu Asn PheIle Phe Ser Tyr 365 370 375 Met Gly Leu Ala Leu Phe Thr Phe Gln Lys HisVal Phe Ser Pro 380 385 390 Ile Phe Ile Ile Gly Ala Phe Val Ala Ile PheLeu Gly Arg Ala 395 400 405 Ala His Ile Tyr Pro Leu Ser Phe Phe Leu AsnLeu Gly Arg Arg 410 415 420 His Lys Ile Gly Trp Asn Phe Gln His Met MetMet Phe Ser Gly 425 430 435 Leu Arg Gly Ala Met Ala Phe Ala Leu Ala IleArg Asp Thr Ala 440 445 450 Ser Tyr Ala Arg Gln Met Met Phe Thr Thr ThrLeu Leu Ile Val 455 460 465 Phe Phe Thr Val Trp Ile Ile Gly Gly Gly ThrThr Pro Met Leu 470 475 480 Ser Trp Leu Asn Ile Arg Val Gly Val Glu GluPro Ser Glu Glu 485 490 495 Asp Gln Asn Glu His His Trp Gln Tyr Phe ArgVal Gly Val Asp 500 505 510 Pro Asp Gln Asp Pro Pro Pro Asn Asn Asp SerPhe Gln Val Leu 515 520 525 Gln Gly Asp Gly Pro Asp Ser Ala Arg Gly AsnArg Thr Lys Gln 530 535 540 Glu Ser Ala Trp Ile Phe Arg Leu Trp Tyr SerPhe Asp His Asn 545 550 555 Tyr Leu Lys Pro Ile Leu Thr His Ser Gly ProPro Leu Thr Thr 560 565 570 Thr Leu Pro Ala Trp Cys Gly Leu Leu Ala ArgCys Leu Thr Ser 575 580 585 Pro Gln Val Tyr Asp Asn Gln Glu Pro Leu ArgGlu Glu Asp Ser 590 595 600 Asp Phe Ile Leu Thr Glu Gly Asp Leu Thr LeuThr Tyr Gly Asp 605 610 615 Ser Thr Val Thr Ala Asn Gly Ser Ser Ser SerHis Thr Ala Ser 620 625 630 Thr Ser Leu Glu Gly Ser Arg Arg Thr Lys SerSer Ser Glu Glu 635 640 645 Val Leu Glu Arg Asp Leu Gly Met Gly Asp GlnLys Val Ser Ser 650 655 660 Arg Gly Thr Arg Leu Val Phe Pro Leu Glu AspAsn Ala 665 670 8 576 PRT Homo sapiens misc_feature Incyte ID No7473314CD1 8 Met Glu Gly Ser Gly Gly Gly Ala Gly Glu Arg Ala Pro Leu Leu1 5 10 15 Gly Ala Arg Arg Ala Ala Ala Ala Ala Ala Ala Gly Ala Phe Ala 2025 30 Gly Arg Arg Ala Ala Cys Gly Ala Val Leu Leu Thr Glu Leu Leu 35 4045 Glu Arg Ala Ala Phe Tyr Gly Ile Thr Ser Asn Leu Val Leu Phe 50 55 60Leu Asn Gly Ala Pro Phe Cys Trp Glu Gly Ala Gln Ala Ser Glu 65 70 75 AlaLeu Leu Leu Phe Met Gly Leu Thr Tyr Leu Gly Ser Pro Phe 80 85 90 Gly GlyTrp Leu Ala Asp Ala Arg Leu Gly Arg Ala Arg Ala Ile 95 100 105 Leu LeuSer Leu Ala Leu Tyr Leu Leu Gly Met Leu Ala Phe Pro 110 115 120 Leu LeuAla Ala Pro Ala Thr Arg Ala Ala Leu Cys Gly Ser Ala 125 130 135 Arg LeuLeu Asn Cys Thr Ala Pro Gly Pro Asp Ala Ala Ala Arg 140 145 150 Cys CysSer Pro Ala Thr Phe Ala Gly Leu Val Leu Val Gly Leu 155 160 165 Gly ValAla Thr Val Lys Ala Asn Ile Thr Pro Phe Gly Ala Asp 170 175 180 Gln ValLys Asp Arg Gly Pro Glu Ala Thr Arg Arg Phe Phe Asn 185 190 195 Trp PheTyr Trp Ser Ile Asn Leu Gly Ala Ile Leu Ser Leu Gly 200 205 210 Gly IleAla Tyr Ile Gln Gln Asn Val Ser Phe Val Thr Gly Tyr 215 220 225 Ala IlePro Thr Val Cys Val Gly Leu Ala Phe Val Ala Phe Leu 230 235 240 Cys GlyGln Ser Val Phe Ile Thr Lys Pro Pro Asp Gly Ser Ala 245 250 255 Phe ThrAsp Met Phe Lys Ile Leu Thr Tyr Ser Cys Cys Ser Gln 260 265 270 Lys ArgSer Gly Glu Arg Gln Ser Asn Gly Glu Gly Ile Gly Val 275 280 285 Phe GlnGln Ser Ser Lys Gln Ser Leu Phe Asp Ser Cys Lys Met 290 295 300 Ser HisGly Gly Pro Phe Thr Glu Glu Lys Val Glu Asp Val Lys 305 310 315 Ala LeuVal Lys Ile Val Pro Val Phe Leu Ala Leu Ile Pro Tyr 320 325 330 Trp ThrVal Tyr Phe Gln Met Gln Thr Thr Tyr Val Leu Gln Ser 335 340 345 Leu HisLeu Arg Ile Pro Glu Ile Ser Asn Ile Thr Thr Thr Pro 350 355 360 His ThrLeu Pro Ala Ala Trp Leu Thr Met Phe Asp Ala Val Leu 365 370 375 Ile LeuLeu Leu Ile Pro Leu Lys Asp Lys Leu Val Asp Pro Ile 380 385 390 Leu ArgArg His Gly Leu Leu Pro Ser Ser Leu Lys Arg Ile Ala 395 400 405 Val GlyMet Phe Phe Val Met Cys Ser Ala Phe Ala Ala Gly Ile 410 415 420 Leu GluSer Lys Arg Leu Asn Leu Val Lys Glu Lys Thr Ile Asn 425 430 435 Gln ThrIle Gly Asn Val Val Tyr His Ala Ala Asp Leu Ser Leu 440 445 450 Trp TrpGln Val Pro Gln Tyr Leu Leu Ile Gly Ile Ser Glu Ile 455 460 465 Phe AlaSer Ile Ala Gly Leu Glu Phe Ala Tyr Ser Ala Ala Pro 470 475 480 Lys SerMet Gln Ser Ala Ile Met Gly Leu Phe Phe Phe Phe Ser 485 490 495 Gly ValGly Ser Phe Val Gly Ser Gly Leu Leu Ala Leu Val Ser 500 505 510 Ile LysAla Ile Gly Trp Met Ser Ser His Thr Asp Phe Gly Asn 515 520 525 Ile AsnGly Cys Tyr Leu Asn Tyr Tyr Phe Phe Leu Leu Ala Ala 530 535 540 Ile GlnGly Ala Thr Leu Leu Leu Phe Leu Ile Ile Ser Val Lys 545 550 555 Tyr AspHis His Arg Asp His Gln Arg Ser Arg Ala Asn Gly Val 560 565 570 Pro ThrSer Arg Arg Ala 575 9 550 PRT Homo sapiens misc_feature Incyte ID No70356714CD1 9 Met Ala Phe Ser Lys Leu Leu Glu Gln Ala Gly Gly Val GlyLeu 1 5 10 15 Phe Gln Thr Leu Gln Val Leu Thr Phe Ile Leu Pro Cys LeuMet 20 25 30 Ile Pro Ser Gln Met Leu Leu Glu Asn Phe Ser Ala Ala Ile Pro35 40 45 Gly His Arg Cys Trp Thr His Met Leu Asp Asn Gly Ser Ala Val 5055 60 Ser Thr Asn Met Thr Pro Lys Ala Leu Leu Thr Ile Ser Ile Pro 65 7075 Pro Gly Pro Asn Gln Gly Pro His Gln Cys Arg Arg Phe Arg Gln 80 85 90Pro Gln Trp Gln Leu Leu Asp Pro Asn Ala Thr Ala Thr Ser Trp 95 100 105Ser Glu Ala Asp Thr Glu Pro Cys Val Asp Gly Trp Val Tyr Asp 110 115 120Arg Ser Val Phe Thr Ser Thr Ile Val Ala Lys Trp Asp Leu Val 125 130 135Cys Ser Ser Gln Gly Leu Lys Pro Leu Ser Gln Ser Ile Phe Met 140 145 150Ser Gly Ile Leu Val Gly Ser Phe Ile Trp Gly Leu Leu Ser Tyr 155 160 165Arg Phe Gly Arg Lys Pro Met Leu Ser Trp Cys Cys Leu Gln Leu 170 175 180Ala Val Ala Gly Thr Ser Thr Ile Phe Ala Pro Thr Phe Val Ile 185 190 195Tyr Cys Gly Leu Arg Phe Val Ala Ala Phe Gly Met Ala Gly Ile 200 205 210Phe Leu Ser Ser Leu Thr Leu Met Val Glu Trp Thr Thr Thr Ser 215 220 225Arg Arg Ala Val Thr Met Thr Val Val Gly Cys Ala Phe Ser Ala 230 235 240Gly Gln Ala Ala Leu Gly Gly Leu Ala Phe Ala Leu Arg Asp Trp 245 250 255Arg Thr Leu Gln Leu Ala Ala Ser Val Pro Phe Phe Ala Ile Ser 260 265 270Leu Ile Ser Trp Trp Leu Pro Glu Ser Ala Arg Trp Leu Ile Ile 275 280 285Lys Gly Lys Pro Asp Gln Ala Leu Gln Glu Leu Arg Lys Val Ala 290 295 300Arg Ile Asn Gly His Lys Glu Ala Lys Asn Leu Thr Ile Glu Val 305 310 315Leu Met Ser Ser Val Lys Glu Glu Val Ala Ser Ala Lys Glu Pro 320 325 330Arg Ser Val Leu Asp Leu Phe Cys Val Pro Val Leu Arg Trp Arg 335 340 345Ser Cys Ala Met Leu Val Val Asn Phe Ser Leu Leu Ile Ser Tyr 350 355 360Tyr Gly Leu Val Phe Asp Leu Gln Ser Leu Gly Arg Asp Ile Phe 365 370 375Leu Leu Gln Ala Leu Phe Gly Ala Val Asp Phe Leu Gly Arg Ala 380 385 390Thr Thr Ala Leu Leu Leu Ser Phe Leu Gly Arg Arg Thr Ile Gln 395 400 405Ala Gly Ser Gln Ala Met Ala Gly Leu Ala Ile Leu Ala Asn Met 410 415 420Leu Val Pro Gln Asp Leu Gln Thr Leu Arg Val Val Phe Ala Val 425 430 435Leu Gly Lys Gly Cys Phe Gly Ile Ser Leu Thr Cys Leu Thr Ile 440 445 450Tyr Lys Ala Glu Leu Phe Pro Thr Pro Val Arg Met Thr Ala Asp 455 460 465Gly Ile Leu His Thr Val Gly Arg Leu Gly Ala Met Met Gly Pro 470 475 480Leu Ile Leu Met Ser Arg Gln Ala Leu Pro Leu Leu Pro Pro Leu 485 490 495Leu Tyr Gly Val Ile Ser Ile Ala Ser Ser Leu Val Val Leu Phe 500 505 510Phe Leu Pro Glu Thr Gln Gly Leu Pro Leu Pro Asp Thr Ile Gln 515 520 525Asp Leu Glu Ser Gln Lys Ser Thr Ala Ala Gln Gly Asn Arg Gln 530 535 540Glu Ala Val Thr Val Glu Ser Thr Ser Leu 545 550 10 559 PRT Homo sapiensmisc_feature Incyte ID No 7611491CD1 10 Met Arg Arg Gln Asp Ser Arg GlyAsn Thr Val Leu His Ala Leu 1 5 10 15 Val Ala Ile Ala Asp Asn Thr ArgGlu Asn Thr Lys Phe Val Thr 20 25 30 Lys Met Tyr Asp Leu Leu Leu Leu LysCys Ala Arg Leu Phe Pro 35 40 45 Asp Ser Asn Leu Glu Ala Val Leu Asn AsnAsp Gly Leu Ser Pro 50 55 60 Leu Met Met Met Ala Ala Lys Thr Gly Lys IleGly Ile Phe Gln 65 70 75 His Ile Ile Arg Arg Glu Val Thr Asp Glu Asp ThrArg His Leu 80 85 90 Ser Arg Lys Phe Lys Asp Trp Ala Tyr Gly Pro Val TyrSer Ser 95 100 105 Leu Tyr Asp Leu Ser Ser Leu Asp Thr Cys Gly Glu GluAla Ser 110 115 120 Val Leu Glu Ile Leu Val Tyr Asn Ser Lys Ile Glu AsnArg His 125 130 135 Glu Met Leu Ala Val Glu Pro Ile Asn Glu Leu Leu ArgAsp Lys 140 145 150 Trp Arg Lys Phe Gly Ala Val Ser Phe Tyr Ile Asn ValVal Ser 155 160 165 Tyr Leu Cys Ala Met Val Ile Phe Thr Leu Thr Ala TyrTyr Gln 170 175 180 Pro Leu Glu Gly Thr Pro Pro Tyr Pro Tyr Arg Thr ThrVal Asp 185 190 195 Tyr Leu Arg Leu Ala Gly Glu Val Ile Thr Leu Phe ThrGly Val 200 205 210 Leu Phe Phe Phe Thr Asn Ile Lys Asp Leu Phe Met LysLys Cys 215 220 225 Pro Gly Val Asn Ser Leu Phe Ile Asp Gly Ser Phe GlnLeu Leu 230 235 240 Tyr Phe Ile Tyr Ser Val Leu Val Ile Val Ser Ala AlaLeu Tyr 245 250 255 Leu Ala Gly Ile Glu Ala Tyr Leu Ala Val Met Val PheAla Leu 260 265 270 Val Leu Gly Trp Met Asn Ala Leu Tyr Phe Thr Arg GlyLeu Lys 275 280 285 Leu Thr Gly Thr Tyr Ser Ile Met Ile Gln Lys Ile LeuPhe Lys 290 295 300 Asp Leu Phe Arg Phe Leu Leu Val Tyr Leu Leu Phe MetIle Gly 305 310 315 Tyr Ala Ser Ala Leu Val Ser Leu Leu Asn Pro Cys AlaAsn Met 320 325 330 Lys Val Cys Asn Glu Asp Gln Thr Asn Cys Thr Val ProThr Tyr 335 340 345 Pro Ser Cys Arg Asp Ser Glu Thr Phe Ser Thr Phe LeuLeu Asp 350 355 360 Leu Phe Lys Leu Thr Ile Gly Met Gly Asp Leu Glu MetLeu Ser 365 370 375 Ser Thr Lys Tyr Pro Val Val Phe Ile Ile Leu Leu ValThr Tyr 380 385 390 Ile Ile Leu Thr Phe Val Leu Leu Leu Asn Met Leu IleAla Leu 395 400 405 Met Gly Glu Thr Val Gly Gln Val Ser Lys Glu Ser LysHis Ile 410 415 420 Trp Lys Leu Gln Trp Ala Thr Thr Ile Leu Asp Ile GluArg Ser 425 430 435 Phe Pro Val Phe Leu Arg Lys Ala Phe Arg Ser Gly GluMet Val 440 445 450 Thr Val Gly Lys Ser Ser Asp Gly Thr Pro Asp Arg ArgTrp Cys 455 460 465 Phe Arg Val Asp Glu Val Asn Trp Ser His Trp Asn GlnAsn Leu 470 475 480 Gly Ile Ile Asn Glu Asp Pro Gly Lys Asn Glu Thr TyrGln Tyr 485 490 495 Tyr Gly Phe Ser His Thr Val Gly Arg Leu Arg Arg AspArg Trp 500 505 510 Ser Ser Val Val Pro Arg Val Val Glu Leu Asn Lys AsnSer Asn 515 520 525 Pro Asp Glu Val Val Val Pro Leu Asp Ser Thr Gly AsnPro Arg 530 535 540 Cys Asp Gly His Gln Gln Gly Tyr Pro Arg Lys Trp ArgThr Asp 545 550 555 Asp Ala Pro Leu 11 181 PRT Homo sapiens misc_featureIncyte ID No 171968CD1 11 Met Phe His His Gln Gln Ala Tyr Cys Leu AlaPro Phe Asp Leu 1 5 10 15 Ile Lys Val Arg Leu Gln Asn Gln Thr Glu ProArg Ala Gln Pro 20 25 30 Gly Ser Pro Pro Pro Arg Tyr Gln Gly Pro Val HisCys Ala Ala 35 40 45 Ser Ile Phe Arg Glu Glu Gly Pro Arg Gly Leu Phe ArgGly Ala 50 55 60 Trp Ala Leu Thr Leu Arg Asp Thr Pro Thr Val Gly Ile TyrPhe 65 70 75 Ile Thr Tyr Glu Gly Leu Cys Arg Gln Tyr Thr Pro Glu Gly Gln80 85 90 Asn Pro Ser Ser Ala Thr Val Leu Val Ala Gly Gly Phe Ala Gly 95100 105 Ile Ala Ser Trp Val Ala Ala Thr Pro Leu Asp Val Ile Lys Ser 110115 120 Arg Met Gln Met Asp Gly Leu Arg Arg Arg Val Tyr Gln Gly Met 125130 135 Leu Asp Cys Met Val Ser Ser Ile Arg Gln Glu Gly Leu Gly Val 140145 150 Phe Phe Arg Gly Val Thr Ile Asn Ser Ala Arg Ala Phe Pro Val 155160 165 Asn Ala Val Thr Phe Leu Ser Tyr Glu Tyr Leu Leu Arg Trp Trp 170175 180 Gly 12 124 PRT Homo sapiens misc_feature Incyte ID No 257274CD112 Met Cys Ser Gly Leu Leu Glu Leu Leu Leu Pro Ile Trp Leu Ser 1 5 10 15Trp Thr Leu Gly Thr Arg Gly Ser Glu Pro Arg Ser Val Asn Asp 20 25 30 ProGly Asn Met Ser Phe Val Lys Glu Thr Val Asp Lys Leu Leu 35 40 45 Lys GlyTyr Asp Ile Arg Leu Arg Pro Asp Phe Gly Gly Pro Pro 50 55 60 Val Cys ValGly Met Asn Ile Asp Ile Ala Ser Ile Asp Met Val 65 70 75 Ser Glu Val AsnMet Arg Phe Trp Leu Gln Glu Arg Gly Thr Lys 80 85 90 Thr Val Val Cys AlaPhe Gln Gly Cys Leu Cys Gly Phe Ser Lys 95 100 105 Ala Ala Ser Trp ThrGly Arg Pro Gly Pro Gly Thr Ala Ser Leu 110 115 120 Cys Pro Arg Cys 132009 PRT Homo sapiens misc_feature Incyte ID No 6355991CD1 13 Met GluGln Thr Val Leu Val Pro Pro Gly Pro Asp Ser Phe Asn 1 5 10 15 Phe PheThr Arg Glu Ser Leu Ala Ala Ile Glu Arg Arg Ile Ala 20 25 30 Glu Glu LysAla Lys Asn Pro Lys Pro Asp Lys Lys Asp Asp Asp 35 40 45 Glu Asn Gly ProLys Pro Asn Ser Asp Leu Glu Ala Gly Lys Asn 50 55 60 Leu Pro Phe Ile TyrGly Asp Ile Pro Pro Glu Met Val Ser Glu 65 70 75 Pro Leu Glu Asp Leu AspPro Tyr Tyr Ile Asn Lys Gln Thr Phe 80 85 90 Ile Val Leu Asn Lys Gly LysAla Ile Phe Arg Phe Ser Ala Thr 95 100 105 Ser Ala Leu Tyr Ile Leu ThrPro Phe Asn Pro Leu Arg Lys Ile 110 115 120 Ala Ile Lys Ile Leu Val HisSer Leu Phe Ser Met Leu Ile Met 125 130 135 Cys Thr Ile Leu Thr Asn CysVal Phe Met Thr Met Ser Asn Pro 140 145 150 Pro Asp Trp Thr Lys Asn ValGlu Tyr Thr Phe Thr Gly Ile Tyr 155 160 165 Thr Phe Glu Ser Leu Ile LysIle Ile Ala Arg Gly Phe Cys Leu 170 175 180 Glu Asp Phe Thr Phe Leu ArgAsp Pro Trp Asn Trp Leu Asp Phe 185 190 195 Thr Val Ile Thr Phe Ala TyrVal Thr Glu Phe Val Asp Leu Gly 200 205 210 Asn Val Ser Ala Leu Arg ThrPhe Arg Val Leu Arg Ala Leu Lys 215 220 225 Thr Ile Ser Val Ile Pro GlyLeu Lys Thr Ile Val Gly Ala Leu 230 235 240 Ile Gln Ser Val Lys Lys LeuSer Asp Val Met Ile Leu Thr Val 245 250 255 Phe Cys Leu Ser Val Phe AlaLeu Ile Gly Leu Gln Leu Phe Met 260 265 270 Gly Asn Leu Arg Asn Lys CysIle Gln Trp Pro Pro Thr Asn Ala 275 280 285 Ser Leu Glu Glu His Ser IleGlu Lys Asn Ile Thr Val Asn Tyr 290 295 300 Asn Gly Thr Leu Ile Asn GluThr Val Phe Glu Phe Asp Trp Lys 305 310 315 Ser Tyr Ile Gln Asp Ser GlyTyr His Tyr Phe Leu Glu Gly Phe 320 325 330 Leu Asp Ala Leu Leu Cys GlyAsn Ser Ser Asp Ala Gly Gln Cys 335 340 345 Pro Glu Gly Tyr Met Cys ValLys Ala Gly Arg Asn Pro Asn Tyr 350 355 360 Gly Tyr Thr Ser Phe Asp ThrPhe Ser Trp Ala Phe Leu Ser Leu 365 370 375 Phe Arg Leu Met Thr Gln AspPhe Trp Glu Asn Leu Tyr Gln Leu 380 385 390 Thr Leu Arg Ala Ala Gly LysThr Tyr Met Ile Phe Phe Val Leu 395 400 405 Val Ile Phe Leu Gly Ser PheTyr Leu Ile Asn Leu Ile Leu Ala 410 415 420 Val Val Ala Met Ala Tyr GluGlu Gln Asn Gln Ala Thr Leu Glu 425 430 435 Glu Ala Glu Gln Lys Glu AlaGlu Phe Gln Gln Met Ile Glu Gln 440 445 450 Leu Lys Lys Gln Gln Glu AlaAla Gln Gln Ala Ala Thr Ala Thr 455 460 465 Ala Ser Glu His Ser Arg GluPro Ser Ala Ala Gly Arg Leu Ser 470 475 480 Asp Ser Ser Ser Glu Ala SerLys Leu Ser Ser Lys Ser Ala Lys 485 490 495 Glu Arg Arg Asn Arg Arg LysLys Arg Lys Gln Lys Glu Gln Ser 500 505 510 Gly Gly Glu Glu Lys Asp GluAsp Glu Phe Gln Lys Ser Glu Ser 515 520 525 Glu Asp Ser Ile Arg Arg LysGly Phe Arg Phe Ser Ile Glu Gly 530 535 540 Asn Arg Leu Thr Tyr Glu LysArg Tyr Ser Ser Pro His Gln Ser 545 550 555 Leu Leu Ser Ile Arg Gly SerLeu Phe Ser Pro Arg Arg Asn Ser 560 565 570 Arg Thr Ser Leu Phe Ser PheArg Gly Arg Ala Lys Asp Val Gly 575 580 585 Ser Glu Asn Asp Phe Ala AspAsp Glu His Ser Thr Phe Glu Asp 590 595 600 Asn Glu Ser Arg Arg Asp SerLeu Phe Val Pro Arg Arg His Gly 605 610 615 Glu Arg Arg Asn Ser Asn LeuSer Gln Thr Ser Arg Ser Ser Arg 620 625 630 Met Leu Ala Val Phe Pro AlaAsn Gly Lys Met His Ser Thr Val 635 640 645 Asp Cys Asn Gly Val Val SerLeu Val Gly Gly Pro Ser Val Pro 650 655 660 Thr Ser Pro Val Gly Gln LeuLeu Pro Glu Val Ile Ile Asp Lys 665 670 675 Pro Ala Thr Asp Asp Asn GlyThr Thr Thr Glu Thr Glu Met Arg 680 685 690 Lys Arg Arg Ser Ser Ser PheHis Val Ser Met Asp Phe Leu Glu 695 700 705 Asp Pro Ser Gln Arg Gln ArgAla Met Ser Ile Ala Ser Ile Leu 710 715 720 Thr Asn Thr Val Glu Glu LeuGlu Glu Ser Arg Gln Lys Cys Pro 725 730 735 Pro Cys Trp Tyr Lys Phe SerAsn Ile Phe Leu Ile Trp Asp Cys 740 745 750 Ser Pro Tyr Trp Leu Lys ValLys His Val Val Asn Leu Val Val 755 760 765 Met Asp Pro Phe Val Asp LeuAla Ile Thr Ile Cys Ile Val Leu 770 775 780 Asn Thr Leu Phe Met Ala MetGlu His Tyr Pro Met Thr Asp His 785 790 795 Phe Asn Asn Val Leu Thr ValGly Asn Leu Val Phe Thr Gly Ile 800 805 810 Phe Thr Ala Glu Met Phe LeuLys Ile Ile Ala Met Asp Pro Tyr 815 820 825 Tyr Tyr Phe Gln Glu Gly TrpAsn Ile Phe Asp Gly Phe Ile Val 830 835 840 Thr Leu Ser Leu Val Glu LeuGly Leu Ala Asn Val Glu Gly Leu 845 850 855 Ser Val Leu Arg Ser Phe ArgLeu Leu Arg Val Phe Lys Leu Ala 860 865 870 Lys Ser Trp Pro Thr Leu AsnMet Leu Ile Lys Ile Ile Gly Asn 875 880 885 Ser Gly Gly Ala Leu Gly AsnLeu Thr Leu Val Leu Ala Ile Ile 890 895 900 Val Phe Ile Phe Ala Val ValGly Met Gln Leu Phe Gly Lys Ser 905 910 915 Tyr Lys Asp Cys Val Cys LysIle Ala Ser Asp Cys Gln Leu Pro 920 925 930 Arg Trp His Met Asn Asp PhePhe His Ser Phe Leu Ile Val Phe 935 940 945 Arg Val Leu Cys Gly Glu TrpIle Glu Thr Met Trp Asp Cys Met 950 955 960 Glu Val Ala Gly Gln Ala MetCys Leu Thr Val Phe Met Met Val 965 970 975 Met Val Ile Gly Asn Leu ValVal Leu Asn Leu Phe Leu Ala Leu 980 985 990 Leu Leu Ser Ser Phe Ser AlaAsp Asn Leu Ala Ala Thr Asp Asp 995 1000 1005 Asp Asn Glu Met Asn AsnLeu Gln Ile Ala Val Asp Arg Met His 1010 1015 1020 Lys Gly Val Ala TyrVal Lys Arg Lys Ile Tyr Glu Phe Ile Gln 1025 1030 1035 Gln Ser Phe IleArg Lys Gln Lys Ile Leu Asp Glu Ile Lys Pro 1040 1045 1050 Leu Asp AspLeu Asn Asn Lys Lys Asp Ser Cys Met Ser Asn His 1055 1060 1065 Thr AlaGlu Ile Gly Lys Asp Leu Asp Tyr Leu Lys Asp Val Asn 1070 1075 1080 GlyThr Thr Ser Gly Ile Gly Thr Gly Ser Ser Val Glu Lys Tyr 1085 1090 1095Ile Ile Asp Glu Ser Asp Tyr Met Ser Phe Ile Asn Asn Pro Ser 1100 11051110 Leu Thr Val Thr Val Pro Ile Ala Val Gly Glu Ser Asp Phe Glu 11151120 1125 Asn Leu Asn Thr Glu Asp Phe Ser Ser Glu Ser Asp Leu Glu Glu1130 1135 1140 Ser Lys Glu Lys Leu Asn Glu Ser Ser Ser Ser Ser Glu GlySer 1145 1150 1155 Thr Val Asp Ile Gly Ala Pro Val Glu Glu Gln Pro ValVal Glu 1160 1165 1170 Pro Glu Glu Thr Leu Glu Pro Glu Ala Cys Phe ThrGlu Gly Cys 1175 1180 1185 Val Gln Arg Phe Lys Cys Cys Gln Ile Asn ValGlu Glu Gly Arg 1190 1195 1200 Gly Lys Gln Trp Trp Asn Leu Arg Arg ThrCys Phe Arg Ile Val 1205 1210 1215 Glu His Asn Trp Phe Glu Thr Phe IleVal Phe Met Ile Leu Leu 1220 1225 1230 Ser Ser Gly Ala Leu Ala Phe GluAsp Ile Tyr Ile Asp Gln Arg 1235 1240 1245 Lys Thr Ile Lys Thr Met LeuGlu Tyr Ala Asp Lys Val Phe Thr 1250 1255 1260 Tyr Ile Phe Ile Leu GluMet Leu Leu Lys Trp Val Ala Tyr Gly 1265 1270 1275 Tyr Gln Thr Tyr PheThr Asn Ala Trp Cys Trp Leu Asp Phe Leu 1280 1285 1290 Ile Val Asp ValSer Leu Val Ser Leu Thr Ala Asn Ala Leu Gly 1295 1300 1305 Tyr Ser GluLeu Gly Ala Ile Lys Ser Leu Arg Thr Leu Arg Ala 1310 1315 1320 Leu ArgPro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg Val 1325 1330 1335 ValVal Asn Ala Leu Leu Gly Ala Ile Pro Ser Ile Met Asn Val 1340 1345 1350Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met Gly 1355 13601365 Val Asn Leu Phe Ala Gly Lys Phe Tyr His Cys Ile Asn Thr Thr 13701375 1380 Thr Gly Asp Arg Phe Asp Ile Glu Asp Val Asn Asn His Thr Asp1385 1390 1395 Cys Leu Lys Leu Ile Glu Arg Asn Glu Thr Ala Arg Trp LysAsn 1400 1405 1410 Val Lys Val Asn Phe Asp Asn Val Gly Phe Gly Tyr LeuSer Leu 1415 1420 1425 Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp IleMet Tyr Ala 1430 1435 1440 Ala Val Asp Ser Arg Asn Val Glu Leu Gln ProLys Tyr Glu Glu 1445 1450 1455 Ser Leu Tyr Met Tyr Leu Tyr Phe Val IlePhe Ile Ile Phe Gly 1460 1465 1470 Ser Phe Phe Thr Leu Asn Leu Phe IleGly Val Ile Ile Asp Asn 1475 1480 1485 Phe Asn Gln Gln Lys Lys Lys PheGly Gly Gln Asp Ile Phe Met 1490 1495 1500 Thr Glu Glu Gln Lys Lys TyrTyr Asn Ala Met Lys Lys Leu Gly 1505 1510 1515 Ser Lys Lys Pro Gln LysPro Ile Pro Arg Pro Gly Asn Lys Phe 1520 1525 1530 Gln Gly Met Val PheAsp Phe Val Thr Arg Gln Val Phe Asp Ile 1535 1540 1545 Ser Ile Met IleLeu Ile Cys Leu Asn Met Val Thr Met Met Val 1550 1555 1560 Glu Thr AspAsp Gln Ser Glu Tyr Val Thr Thr Ile Leu Ser Arg 1565 1570 1575 Ile AsnLeu Val Phe Ile Val Leu Phe Thr Gly Glu Cys Val Leu 1580 1585 1590 LysLeu Ile Ser Leu Arg His Tyr Tyr Phe Thr Ile Gly Trp Asn 1595 1600 1605Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val Gly Met Phe 1610 16151620 Leu Ala Glu Leu Ile Glu Lys Tyr Phe Val Ser Pro Thr Leu Phe 16251630 1635 Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu Ile1640 1645 1650 Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu MetMet 1655 1660 1665 Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu PheLeu Val 1670 1675 1680 Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn PheAla Tyr Val 1685 1690 1695 Lys Arg Glu Val Gly Ile Asp Asp Met Phe AsnPhe Glu Thr Phe 1700 1705 1710 Gly Asn Ser Met Ile Cys Leu Phe Gln IleThr Thr Ser Ala Gly 1715 1720 1725 Trp Asp Gly Leu Leu Ala Pro Ile LeuAsn Ser Lys Pro Pro Asp 1730 1735 1740 Cys Asp Pro Asn Lys Val Asn ProGly Ser Ser Val Lys Gly Asp 1745 1750 1755 Cys Gly Asn Pro Ser Val GlyIle Phe Phe Phe Val Ser Tyr Ile 1760 1765 1770 Ile Ile Ser Phe Leu ValVal Val Asn Met Tyr Ile Ala Val Ile 1775 1780 1785 Leu Glu Asn Phe SerVal Ala Thr Glu Glu Ser Ala Glu Pro Leu 1790 1795 1800 Ser Glu Asp AspPhe Glu Met Phe Tyr Glu Val Trp Glu Lys Phe 1805 1810 1815 Asp Pro AspAla Thr Gln Phe Met Glu Phe Glu Lys Leu Ser Gln 1820 1825 1830 Phe AlaAla Ala Leu Glu Pro Pro Leu Asn Leu Pro Gln Pro Asn 1835 1840 1845 LysLeu Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly Asp 1850 1855 1860Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg Val 1865 18701875 Leu Gly Glu Ser Gly Glu Met Asp Ala Leu Arg Ile Gln Met Glu 18801885 1890 Glu Arg Phe Met Ala Ser Asn Pro Ser Lys Val Ser Tyr Gln Pro1895 1900 1905 Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu Val Ser AlaVal 1910 1915 1920 Ile Ile Gln Arg Ala Tyr Arg Arg His Leu Leu Lys ArgThr Val 1925 1930 1935 Lys Gln Ala Ser Phe Thr Tyr Asn Lys Asn Lys IleLys Gly Gly 1940 1945 1950 Ala Asn Leu Leu Ile Lys Glu Asp Met Ile IleAsp Arg Ile Asn 1955 1960 1965 Glu Asn Ser Ile Thr Glu Lys Thr Asp LeuThr Met Ser Thr Ala 1970 1975 1980 Ala Cys Pro Pro Ser Tyr Asp Arg ValThr Lys Pro Ile Val Glu 1985 1990 1995 Lys His Glu Gln Glu Gly Lys AspGlu Lys Ala Lys Gly Lys 2000 2005 14 538 PRT Homo sapiens misc_featureIncyte ID No 70035348CD1 14 Met Val Pro Val Glu Asn Thr Glu Gly Pro SerLeu Leu Asn Gln 1 5 10 15 Lys Gly Thr Ala Val Glu Thr Glu Gly Ser GlySer Arg His Pro 20 25 30 Pro Trp Ala Arg Gly Cys Gly Met Phe Thr Phe LeuSer Ser Val 35 40 45 Thr Ala Ala Val Ser Gly Leu Leu Val Gly Tyr Glu LeuGly Ile 50 55 60 Ile Ser Gly Ala Leu Leu Gln Ile Lys Thr Leu Leu Ala LeuSer 65 70 75 Cys His Glu Gln Glu Met Val Val Ser Ser Leu Val Ile Gly Ala80 85 90 Leu Leu Ala Ser Leu Thr Gly Gly Val Leu Ile Asp Arg Tyr Gly 95100 105 Arg Arg Thr Ala Ile Ile Leu Ser Ser Cys Leu Leu Gly Leu Gly 110115 120 Ser Leu Val Leu Ile Leu Ser Leu Ser Tyr Thr Val Leu Ile Val 125130 135 Gly Arg Ile Ala Ile Gly Val Ser Ile Ser Leu Ser Ser Ile Ala 140145 150 Thr Cys Val Tyr Ile Ala Glu Ile Ala Pro Gln His Arg Arg Gly 155160 165 Leu Leu Val Ser Leu Asn Glu Leu Met Ile Val Ile Gly Ile Leu 170175 180 Ser Ala Tyr Ile Ser Asn Tyr Ala Phe Ala Asn Val Phe His Gly 185190 195 Trp Lys Tyr Met Phe Gly Leu Val Ile Pro Leu Gly Val Leu Gln 200205 210 Ala Ile Ala Met Tyr Phe Leu Pro Pro Ser Pro Arg Phe Leu Val 215220 225 Met Lys Gly Gln Glu Gly Ala Ala Ser Lys Val Leu Gly Arg Leu 230235 240 Arg Ala Leu Ser Asp Thr Thr Glu Glu Leu Thr Val Ile Lys Ser 245250 255 Ser Leu Lys Asp Glu Tyr Gln Tyr Ser Phe Trp Asp Leu Phe Arg 260265 270 Ser Lys Asp Asn Met Arg Thr Arg Ile Met Ile Gly Leu Thr Leu 275280 285 Val Phe Phe Val Gln Ile Thr Gly Gln Pro Asn Ile Leu Phe Tyr 290295 300 Ala Ser Thr Val Leu Lys Ser Val Gly Phe Gln Ser Asn Glu Ala 305310 315 Ala Ser Leu Ala Ser Thr Gly Val Gly Val Val Lys Val Ile Ser 320325 330 Thr Ile Pro Ala Thr Leu Leu Val Asp His Val Gly Ser Lys Thr 335340 345 Phe Leu Cys Ile Gly Ser Ser Val Met Ala Ala Ser Leu Val Thr 350355 360 Met Gly Ile Val Asn Leu Asn Ile His Met Asn Phe Thr His Ile 365370 375 Cys Arg Ser His Asn Ser Ile Asn Gln Ser Leu Asp Glu Ser Val 380385 390 Ile Tyr Gly Pro Gly Asn Leu Ser Thr Asn Asn Asn Thr Leu Arg 395400 405 Asp His Phe Lys Gly Ile Ser Ser His Ser Arg Ser Ser Leu Met 410415 420 Pro Leu Arg Asn Asp Val Asp Lys Arg Gly Glu Thr Thr Ser Ala 425430 435 Ser Leu Leu Asn Ala Gly Leu Ser His Thr Glu Tyr Gln Ile Val 440445 450 Thr Asp Pro Gly Asp Val Pro Ala Phe Leu Lys Trp Leu Ser Leu 455460 465 Ala Ser Leu Leu Val Tyr Val Ala Ala Phe Ser Ile Gly Leu Gly 470475 480 Pro Arg Asp Val Ile Phe Ile Gly Gln Ser Thr Asn Leu Pro Ser 485490 495 Ala Pro Glu Gly Asp Thr Ile Ser Ile Ser Lys Thr Ile Tyr Tyr 500505 510 Ala Ala Tyr Asn Lys Ala Ile Ile Gln Thr Ala Leu Glu Arg Gln 515520 525 Pro Arg Ala Lys Thr Val Ser Ala Phe Ser His Lys Thr 530 535 15742 PRT Homo sapiens misc_feature Incyte ID No 7472539CD1 15 Met Glu TyrGln Ala Ser Glu Val Ile Gly Gln Arg Gln Ser Ser 1 5 10 15 Ala Thr LysPro Gly Arg Ser Gly Lys Glu Ser Val Thr Glu Pro 20 25 30 Trp Ala Arg ValPro Gly Ala Leu Gly Val Ala Ala Arg Gln Met 35 40 45 His Pro Lys Ser IleIle Thr Phe Arg Glu Ile Asn Gly Glu Tyr 50 55 60 Thr Gly Ala Val Asp PhePro Arg Leu Gly Val Arg Ala Ser Glu 65 70 75 Glu Thr Ala Leu Arg Glu LeuLys Met Ser Lys Glu Leu Ala Ala 80 85 90 Met Gly Pro Gly Ala Ser Gly AspGly Val Arg Thr Glu Thr Ala 95 100 105 Pro His Ile Ala Leu Asp Ser ArgVal Gly Leu His Ala Tyr Asp 110 115 120 Ile Ser Val Val Val Ile Tyr PheVal Phe Val Ile Ala Val Gly 125 130 135 Ile Trp Ser Ser Ile Arg Ala SerArg Gly Thr Ile Gly Gly Tyr 140 145 150 Phe Leu Ala Gly Ser Trp Ser IleSer Asp Val Gln Gln Cys Gly 155 160 165 Gln Trp Leu Val His Arg Pro GlyTrp Asp Arg Gly Cys Arg Arg 170 175 180 Pro Cys Arg Arg Trp Leu Arg ValGlu Leu Leu Leu Ala Leu Gly 185 190 195 Trp Val Phe Val Pro Val Tyr IleAla Ala Gly Val Val Thr Met 200 205 210 Pro Gln Tyr Leu Lys Lys Arg PheGly Gly Gln Arg Ile Gln Val 215 220 225 Tyr Met Ser Val Leu Ser Leu IleLeu Tyr Ile Phe Thr Lys Ile 230 235 240 Ser Thr Asp Ile Phe Ser Gly AlaLeu Phe Ile Gln Met Ala Leu 245 250 255 Gly Trp Asn Leu Tyr Leu Ser ThrGly Ile Leu Leu Val Val Thr 260 265 270 Ala Val Tyr Thr Ile Ala Gly GlyLeu Met Ala Val Ile Tyr Thr 275 280 285 Asp Ala Leu Gln Thr Val Ile MetVal Gly Gly Ala Leu Val Leu 290 295 300 Met Phe Leu Gly Phe Gln Asp ValGly Trp Tyr Pro Gly Leu Glu 305 310 315 Gln Arg Tyr Arg Gln Ala Ile ProAsn Val Thr Val Pro Asn Thr 320 325 330 Thr Cys His Leu Pro Arg Pro AspAla Phe His Ile Leu Arg Asp 335 340 345 Pro Val Ser Gly Asp Ile Pro TrpPro Gly Leu Ile Phe Gly Leu 350 355 360 Thr Val Leu Ala Thr Trp Cys TrpCys Thr Asp Gln Val Ile Val 365 370 375 Gln Arg Ser Leu Ser Ala Lys SerLeu Ser His Ala Lys Gly Gly 380 385 390 Ser Val Leu Gly Gly Tyr Leu LysIle Leu Pro Met Phe Phe Ile 395 400 405 Val Met Pro Gly Met Ile Ser ArgAla Leu Phe Pro Asp Glu Val 410 415 420 Gly Cys Val Asp Pro Asp Val CysGln Arg Ile Cys Gly Ala Arg 425 430 435 Val Gly Cys Ser Asn Ile Ala TyrPro Lys Leu Val Met Ala Leu 440 445 450 Met Pro Val Gly Leu Arg Gly LeuMet Ile Ala Val Ile Met Ala 455 460 465 Ala Leu Met Ser Ser Leu Thr SerIle Phe Asn Ser Ser Ser Thr 470 475 480 Leu Phe Thr Ile Asp Val Trp GlnArg Phe Arg Arg Lys Ser Thr 485 490 495 Glu Gln Glu Leu Met Val Val GlyArg Val Phe Val Val Phe Leu 500 505 510 Val Val Ile Ser Ile Leu Trp IlePro Ile Ile Gln Ser Ser Asn 515 520 525 Ser Gly Gln Leu Phe Asp Tyr IleGln Ala Val Thr Ser Tyr Leu 530 535 540 Ala Pro Pro Ile Thr Ala Leu PheLeu Leu Ala Ile Phe Cys Lys 545 550 555 Arg Val Thr Glu Pro Gly Ala PheTrp Gly Leu Val Phe Gly Leu 560 565 570 Gly Val Gly Leu Leu Arg Met IleLeu Glu Phe Ser Tyr Pro Ala 575 580 585 Pro Ala Cys Gly Glu Val Asp ArgArg Pro Ala Val Leu Lys Asp 590 595 600 Phe His Tyr Leu Tyr Phe Ala IleLeu Leu Cys Gly Leu Thr Ala 605 610 615 Ile Val Ile Val Ile Leu Thr ArgLeu Thr Trp Trp Thr Arg Asn 620 625 630 Cys Pro Leu Ser Glu Leu Glu LysGlu Ala His Glu Ser Thr Pro 635 640 645 Glu Ile Ser Glu Arg Pro Ala GlyGlu Cys Pro Ala Gly Gly Gly 650 655 660 Ala Ala Glu Asn Ser Ser Leu GlyGln Glu Gln Pro Glu Ala Pro 665 670 675 Ser Arg Ser Trp Gly Lys Leu LeuTrp Ser Trp Phe Cys Gly Leu 680 685 690 Ser Gly Thr Pro Glu Gln Ala LeuSer Pro Ala Glu Lys Ala Ala 695 700 705 Leu Glu Gln Lys Leu Thr Ser IleGlu Glu Glu Pro Leu Trp Arg 710 715 720 His Val Cys Asn Ile Asn Ala ValLeu Leu Leu Ala Ile Asn Ile 725 730 735 Phe Leu Trp Gly Tyr Phe Ala 74016 426 PRT Homo sapiens misc_feature Incyte ID No 817477CD1 16 Met AlaArg Arg Thr Glu Pro Pro Asp Gly Gly Trp Gly Trp Val 1 5 10 15 Val ValLeu Ser Ala Phe Phe Gln Ser Ala Leu Val Phe Gly Val 20 25 30 Leu Arg SerPhe Gly Val Phe Phe Val Glu Phe Val Ala Ala Phe 35 40 45 Glu Glu Gln AlaAla Arg Val Ser Trp Ile Ala Ser Ile Gly Ile 50 55 60 Ala Val Gln Gln PheGly Ser Pro Val Gly Ser Ala Leu Ser Thr 65 70 75 Lys Phe Gly Pro Arg ProVal Val Met Thr Gly Gly Ile Leu Ala 80 85 90 Ala Leu Gly Met Leu Leu AlaSer Phe Ala Thr Ser Leu Thr His 95 100 105 Leu Tyr Leu Ser Ile Gly LeuLeu Ser Gly Ser Gly Trp Ala Leu 110 115 120 Thr Phe Ala Pro Thr Leu AlaCys Leu Ser Cys Tyr Phe Ser Arg 125 130 135 Arg Arg Ser Leu Ala Thr GlyLeu Ala Leu Thr Gly Val Gly Leu 140 145 150 Ser Ser Phe Thr Phe Ala ProPhe Phe Gln Trp Leu Leu Ser His 155 160 165 Tyr Ala Trp Arg Gly Ser LeuLeu Leu Val Ser Ala Leu Ser Leu 170 175 180 His Leu Val Ala Cys Gly AlaLeu Leu Arg Pro Pro Ser Leu Ala 185 190 195 Glu Asp Pro Ala Val Gly GlyPro Arg Ala Gln Leu Thr Ser Leu 200 205 210 Leu His His Gly Pro Phe LeuArg Tyr Thr Val Ala Leu Thr Leu 215 220 225 Ile Asn Thr Gly Tyr Phe IlePro Tyr Leu His Leu Val Ala His 230 235 240 Leu Gln Asp Leu Asp Trp AspPro Leu Pro Ala Ala Phe Leu Leu 245 250 255 Ser Val Val Ala Ile Ser AspLeu Val Gly Arg Val Val Ser Gly 260 265 270 Trp Leu Gly Asp Ala Val ProGly Pro Val Thr Arg Leu Leu Met 275 280 285 Leu Trp Thr Thr Leu Thr GlyVal Ser Leu Ala Leu Phe Pro Val 290 295 300 Ala Gln Ala Pro Thr Ala LeuVal Ala Leu Ala Val Ala Tyr Gly 305 310 315 Phe Thr Ser Gly Ala Leu AlaPro Leu Ala Phe Ser Val Leu Pro 320 325 330 Glu Leu Ile Gly Thr Arg ArgIle Tyr Cys Gly Leu Gly Leu Leu 335 340 345 Gln Met Ile Glu Ser Ile GlyGly Leu Leu Gly Pro Pro Leu Ser 350 355 360 Gly Tyr Leu Arg Asp Val ThrGly Asn Tyr Thr Ala Ser Phe Val 365 370 375 Val Ala Gly Ala Phe Leu LeuSer Gly Ser Gly Ile Leu Leu Thr 380 385 390 Leu Pro His Phe Phe Cys PheSer Thr Thr Thr Ser Gly Pro Gln 395 400 405 Asp Leu Val Thr Glu Ala LeuAsp Thr Lys Val Pro Leu Pro Lys 410 415 420 Glu Gly Leu Glu Glu Asp 42517 1197 PRT Homo sapiens misc_feature Incyte ID No 1442166CD1 17 Met AlaAla Ala Ala Ala Val Gly Asn Ala Val Pro Cys Gly Ala 1 5 10 15 Arg ProCys Gly Val Arg Pro Asp Gly Gln Pro Lys Pro Gly Pro 20 25 30 Gln Pro ArgAla Leu Leu Ala Ala Gly Pro Ala Leu Ile Ala Asn 35 40 45 Gly Asp Glu LeuVal Ala Ala Val Trp Pro Tyr Arg Arg Leu Ala 50 55 60 Leu Leu Arg Arg LeuThr Val Leu Pro Phe Ala Gly Leu Leu Tyr 65 70 75 Pro Ala Trp Leu Gly AlaAla Ala Ala Gly Cys Trp Gly Trp Gly 80 85 90 Ser Ser Trp Val Gln Ile ProGlu Ala Ala Leu Leu Val Leu Ala 95 100 105 Thr Ile Cys Leu Ala His AlaLeu Thr Val Leu Ser Gly His Trp 110 115 120 Ser Val His Ala His Cys AlaLeu Thr Cys Thr Pro Glu Tyr Asp 125 130 135 Pro Ser Lys Ala Thr Phe ValLys Val Val Pro Thr Pro Asn Asn 140 145 150 Gly Ser Thr Glu Leu Val AlaLeu His Arg Asn Glu Gly Glu Asp 155 160 165 Gly Leu Glu Val Leu Ser PheGlu Phe Gln Lys Ile Lys Tyr Ser 170 175 180 Tyr Asp Ala Leu Glu Lys LysGln Phe Leu Pro Val Ala Phe Pro 185 190 195 Val Gly Asn Ala Phe Ser TyrTyr Gln Ser Asn Arg Gly Phe Gln 200 205 210 Glu Asp Ser Glu Ile Arg AlaAla Glu Lys Lys Phe Gly Ser Asn 215 220 225 Lys Ala Glu Met Val Val ProAsp Phe Ser Glu Leu Phe Lys Glu 230 235 240 Arg Ala Thr Ala Pro Phe PheVal Phe Gln Val Phe Cys Val Gly 245 250 255 Leu Trp Cys Leu Asp Glu TyrTrp Tyr Tyr Ser Val Phe Thr Leu 260 265 270 Ser Met Leu Val Ala Phe GluAla Ser Leu Val Gln Gln Gln Met 275 280 285 Arg Asn Met Ser Glu Ile ArgLys Met Gly Asn Lys Pro His Met 290 295 300 Ile Gln Val Tyr Arg Ser ArgLys Trp Arg Pro Ile Ala Ser Asp 305 310 315 Glu Ile Val Pro Gly Asp IleVal Ser Ile Gly Arg Ser Pro Gln 320 325 330 Glu Asn Leu Val Pro Cys AspVal Leu Leu Leu Arg Gly Arg Cys 335 340 345 Ile Val Asp Glu Ala Met LeuThr Gly Glu Ser Val Pro Gln Met 350 355 360 Lys Glu Pro Ile Glu Asp LeuSer Pro Asp Arg Val Leu Asp Leu 365 370 375 Gln Ala Asp Ser Arg Leu HisVal Ile Phe Gly Gly Thr Lys Val 380 385 390 Val Gln His Ile Pro Pro GlnLys Ala Thr Thr Gly Leu Lys Pro 395 400 405 Val Asp Ser Gly Cys Val AlaTyr Val Leu Arg Thr Gly Phe Asn 410 415 420 Thr Ser Gln Gly Lys Leu LeuArg Thr Ile Leu Phe Gly Val Lys 425 430 435 Arg Val Thr Ala Asn Asn LeuGlu Thr Phe Ile Phe Ile Leu Phe 440 445 450 Leu Leu Val Phe Ala Ile AlaAla Ala Ala Tyr Val Trp Ile Glu 455 460 465 Gly Thr Lys Asp Pro Ser ArgAsn Arg Tyr Lys Leu Phe Leu Glu 470 475 480 Cys Thr Leu Ile Leu Thr SerVal Val Pro Pro Glu Leu Pro Ile 485 490 495 Glu Leu Ser Leu Ala Val AsnThr Ser Leu Ile Ala Leu Ala Lys 500 505 510 Leu Tyr Met Tyr Cys Thr GluPro Phe Arg Ile Pro Phe Ala Gly 515 520 525 Lys Val Glu Val Cys Cys PheAsp Lys Thr Gly Thr Leu Thr Ser 530 535 540 Asp Ser Leu Val Val Arg GlyVal Ala Gly Leu Arg Asp Gly Lys 545 550 555 Glu Val Thr Pro Val Ser SerIle Pro Val Glu Thr His Arg Ala 560 565 570 Leu Ala Ser Cys His Ser LeuMet Gln Leu Asp Asp Gly Thr Leu 575 580 585 Val Gly Asp Pro Leu Glu LysAla Met Leu Thr Ala Val Asp Trp 590 595 600 Thr Leu Thr Lys Asp Glu LysVal Phe Pro Arg Ser Ile Lys Thr 605 610 615 Gln Gly Leu Lys Ile His GlnArg Phe His Phe Ala Ser Ala Leu 620 625 630 Lys Arg Met Ser Val Leu AlaSer Tyr Glu Lys Leu Gly Ser Thr 635 640 645 Asp Leu Cys Tyr Ile Ala AlaVal Lys Gly Ala Pro Glu Thr Leu 650 655 660 His Ser Met Phe Ser Gln CysPro Pro Asp Tyr His His Ile His 665 670 675 Thr Glu Ile Ser Arg Glu GlyAla Arg Val Leu Ala Leu Gly Tyr 680 685 690 Lys Glu Leu Gly His Leu ThrHis Gln Gln Ala Arg Glu Val Lys 695 700 705 Arg Glu Ala Leu Glu Cys SerLeu Lys Phe Val Gly Phe Ile Val 710 715 720 Val Ser Cys Pro Leu Lys AlaAsp Ser Lys Ala Val Ile Arg Glu 725 730 735 Ile Gln Asn Ala Ser His ArgVal Val Met Ile Thr Gly Asp Asn 740 745 750 Pro Leu Thr Ala Cys His ValAla Gln Glu Leu His Phe Ile Glu 755 760 765 Lys Ala His Thr Leu Ile LeuGln Pro Pro Ser Glu Lys Gly Arg 770 775 780 Gln Cys Glu Trp Arg Ser IleAsp Gly Ser Ile Val Leu Pro Leu 785 790 795 Ala Arg Gly Ser Pro Lys AlaLeu Ala Leu Glu Tyr Ala Leu Cys 800 805 810 Leu Thr Gly Asp Gly Leu AlaHis Leu Gln Ala Thr Asp Pro Gln 815 820 825 Gln Leu Leu Arg Leu Ile ProHis Val Gln Val Phe Ala Arg Val 830 835 840 Ala Pro Lys Gln Lys Glu PheVal Ile Thr Ser Leu Lys Glu Leu 845 850 855 Gly Tyr Val Thr Leu Met CysGly Asp Gly Thr Asn Asp Val Gly 860 865 870 Ala Leu Lys His Ala Asp ValGly Val Ala Leu Leu Ala Asn Ala 875 880 885 Pro Glu Arg Val Val Glu ArgArg Arg Arg Pro Arg Asp Ser Pro 890 895 900 Thr Leu Ser Asn Ser Gly IleArg Ala Thr Ser Arg Thr Ala Lys 905 910 915 Gln Arg Ser Gly Leu Pro ProSer Glu Glu Gln Pro Thr Ser Gln 920 925 930 Arg Asp Arg Leu Ser Gln ValLeu Arg Asp Leu Glu Asp Glu Ser 935 940 945 Thr Pro Ile Val Lys Leu GlyAsp Ala Ser Ile Ala Ala Pro Phe 950 955 960 Thr Ser Lys Leu Ser Ser IleGln Cys Ile Cys His Val Ile Lys 965 970 975 Gln Gly Arg Cys Thr Leu ValThr Thr Leu Gln Met Phe Lys Ile 980 985 990 Leu Ala Leu Asn Ala Leu IleLeu Ala Tyr Ser Gln Ser Val Leu 995 1000 1005 Tyr Leu Glu Gly Val LysPhe Ser Asp Phe Gln Ala Thr Leu Gln 1010 1015 1020 Gly Leu Leu Leu AlaGly Cys Phe Leu Phe Ile Ser Arg Ser Lys 1025 1030 1035 Pro Leu Lys ThrLeu Ser Arg Glu Arg Pro Leu Pro Asn Ile Phe 1040 1045 1050 Asn Leu TyrThr Ile Leu Thr Val Met Leu Gln Phe Phe Val His 1055 1060 1065 Phe LeuSer Leu Val Tyr Leu Tyr Arg Glu Ala Gln Ala Arg Ser 1070 1075 1080 ProGlu Lys Gln Glu Gln Phe Val Asp Leu Tyr Lys Glu Phe Glu 1085 1090 1095Pro Ser Leu Val Asn Ser Thr Val Tyr Ile Met Ala Met Ala Met 1100 11051110 Gln Met Ala Thr Phe Ala Ile Asn Tyr Lys Gly Pro Pro Phe Met 11151120 1125 Glu Ser Leu Pro Glu Asn Lys Pro Leu Val Trp Ser Leu Ala Val1130 1135 1140 Ser Leu Leu Ala Ile Ile Gly Leu Leu Leu Gly Ser Ser ProAsp 1145 1150 1155 Phe Asn Ser Gln Phe Gly Leu Val Asp Ile Pro Val GluVal Leu 1160 1165 1170 Leu Leu Asp Phe Cys Leu Ala Leu Leu Ala Asp ArgVal Leu Gln 1175 1180 1185 Phe Phe Leu Gly Thr Pro Lys Leu Lys Val ProSer 1190 1195 18 1771 PRT Homo sapiens misc_feature Incyte ID No2311751CD1 18 Met Met Glu Arg Ala Ile Ile Asp Thr Phe Val Gly His AspVal 1 5 10 15 Val Glu Pro Gly Ser Tyr Val Gln Met Phe Pro Tyr Pro CysTyr 20 25 30 Thr Arg Asp Asp Phe Leu Phe Val Ile Glu His Met Met Pro Leu35 40 45 Cys Met Val Ile Ser Trp Val Tyr Ser Val Ala Met Thr Ile Gln 5055 60 His Ile Val Ala Glu Lys Glu His Arg Leu Lys Glu Val Met Lys 65 7075 Thr Met Gly Leu Asn Asn Ala Val His Trp Val Ala Trp Phe Ile 80 85 90Thr Gly Phe Val Gln Leu Ser Ile Ser Val Thr Ala Leu Thr Ala 95 100 105Ile Leu Lys Tyr Gly Gln Val Leu Met His Ser His Val Val Ile 110 115 120Ile Trp Leu Phe Leu Ala Val Tyr Ala Val Ala Thr Ile Met Phe 125 130 135Cys Phe Leu Val Ser Val Leu Tyr Ser Lys Ala Lys Leu Ala Ser 140 145 150Ala Cys Gly Gly Ile Ile Tyr Phe Leu Ser Tyr Val Pro Tyr Met 155 160 165Tyr Val Ala Ile Arg Glu Glu Val Ala His Asp Lys Ile Thr Ala 170 175 180Phe Glu Lys Cys Ile Ala Ser Leu Met Ser Thr Thr Ala Phe Gly 185 190 195Leu Gly Ser Lys Tyr Phe Ala Leu Tyr Glu Val Ala Gly Val Gly 200 205 210Ile Gln Trp His Thr Phe Ser Gln Ser Pro Val Glu Gly Asp Asp 215 220 225Phe Asn Leu Leu Leu Ala Val Thr Met Leu Met Val Asp Ala Val 230 235 240Val Tyr Gly Ile Leu Thr Trp Tyr Ile Glu Ala Val His Pro Gly 245 250 255Met Tyr Gly Leu Pro Arg Pro Trp Tyr Phe Pro Leu Gln Lys Ser 260 265 270Tyr Trp Leu Gly Ser Gly Arg Thr Glu Ala Trp Glu Trp Ser Trp 275 280 285Pro Trp Ala Arg Thr Pro Arg Leu Ser Val Met Glu Glu Asp Gln 290 295 300Ala Cys Ala Met Glu Ser Arg Arg Phe Glu Glu Thr Arg Gly Met 305 310 315Glu Glu Glu Pro Thr His Leu Pro Leu Val Val Cys Val Asp Lys 320 325 330Leu Thr Lys Val Tyr Lys Asp Asp Lys Lys Leu Ala Leu Asn Lys 335 340 345Leu Ser Leu Asn Leu Tyr Glu Asn Gln Val Val Ser Phe Leu Gly 350 355 360His Asn Gly Ala Gly Lys Thr Thr Thr Met Ser Ile Leu Thr Gly 365 370 375Leu Phe Pro Pro Thr Ser Gly Ser Ala Thr Ile Tyr Gly His Asp 380 385 390Ile Arg Thr Glu Met Asp Glu Ile Arg Lys Asn Leu Gly Met Cys 395 400 405Pro Gln His Asn Val Leu Phe Asp Arg Leu Thr Val Glu Glu His 410 415 420Leu Trp Phe Tyr Ser Arg Leu Lys Ser Met Ala Gln Glu Glu Ile 425 430 435Arg Arg Glu Met Asp Lys Met Ile Glu Asp Leu Glu Leu Ser Asn 440 445 450Lys Arg His Ser Leu Val Gln Thr Leu Ser Gly Gly Met Lys Arg 455 460 465Lys Leu Ser Val Ala Ile Ala Phe Val Gly Gly Ser Arg Ala Ile 470 475 480Ile Leu Asp Glu Pro Thr Ala Gly Val Asp Pro Tyr Ala Arg Arg 485 490 495Ala Ile Trp Asp Leu Ile Leu Lys Tyr Lys Pro Gly Arg Thr Ile 500 505 510Leu Leu Ser Thr His His Met Asp Glu Ala Asp Leu Leu Gly Asp 515 520 525Arg Ile Ala Ile Ile Ser His Gly Lys Leu Lys Cys Cys Gly Ser 530 535 540Pro Leu Phe Leu Lys Gly Thr Tyr Gly Asp Gly Tyr Arg Leu Thr 545 550 555Leu Val Lys Arg Pro Ala Glu Pro Gly Gly Pro Gln Glu Pro Gly 560 565 570Leu Ala Ser Ser Pro Pro Gly Arg Ala Pro Leu Ser Ser Cys Ser 575 580 585Glu Leu Gln Val Ser Gln Phe Ile Arg Lys His Val Ala Ser Cys 590 595 600Leu Leu Val Ser Asp Thr Ser Thr Glu Leu Ser Tyr Ile Leu Pro 605 610 615Ser Glu Ala Ala Lys Lys Gly Ala Phe Glu Arg Leu Phe Gln His 620 625 630Leu Glu Arg Ser Leu Asp Ala Leu His Leu Ser Ser Phe Gly Leu 635 640 645Met Asp Thr Thr Leu Glu Glu Val Phe Leu Lys Val Ser Glu Glu 650 655 660Asp Gln Ser Leu Glu Asn Ser Glu Ala Asp Val Lys Glu Ser Arg 665 670 675Lys Asp Val Leu Pro Gly Ala Glu Gly Pro Ala Ser Gly Glu Gly 680 685 690His Ala Gly Asn Leu Ala Arg Cys Ser Glu Leu Thr Gln Ser Gln 695 700 705Ala Ser Leu Gln Ser Ala Ser Ser Val Gly Ser Ala Arg Gly Asp 710 715 720Glu Gly Ala Gly Tyr Thr Asp Val Tyr Gly Asp Tyr Arg Pro Leu 725 730 735Phe Asp Asn Pro Gln Asp Pro Asp Asn Val Ser Leu Gln Glu Val 740 745 750Glu Ala Glu Ala Leu Ser Arg Val Gly Gln Gly Ser Arg Lys Leu 755 760 765Asp Gly Gly Trp Leu Lys Val Arg Gln Phe His Gly Leu Leu Val 770 775 780Lys Arg Phe His Cys Ala Arg Arg Asn Ser Lys Ala Leu Phe Ser 785 790 795Gln Ile Leu Leu Pro Ala Phe Phe Val Cys Val Ala Met Thr Val 800 805 810Ala Leu Ser Val Pro Glu Ile Gly Asp Leu Pro Pro Leu Val Leu 815 820 825Ser Pro Ser Gln Tyr His Asn Tyr Thr Gln Pro Arg Gly Asn Phe 830 835 840Ile Pro Tyr Ala Asn Glu Glu Arg Arg Glu Tyr Arg Leu Arg Leu 845 850 855Ser Pro Asp Ala Ser Pro Gln Gln Leu Val Ser Thr Phe Arg Leu 860 865 870Pro Ser Gly Val Gly Ala Thr Cys Val Leu Lys Ser Pro Ala Asn 875 880 885Gly Ser Leu Gly Pro Thr Leu Asn Leu Ser Ser Gly Glu Ser Arg 890 895 900Leu Leu Ala Ala Arg Phe Phe Asp Ser Met Cys Leu Glu Ser Phe 905 910 915Thr Gln Gly Leu Pro Leu Ser Asn Phe Val Pro Pro Pro Pro Ser 920 925 930Pro Ala Pro Ser Asp Ser Pro Ala Ser Pro Asp Glu Asp Leu Gln 935 940 945Ala Trp Asn Val Ser Leu Pro Pro Thr Ala Gly Pro Glu Met Trp 950 955 960Thr Ser Ala Pro Ser Leu Pro Arg Leu Val Arg Glu Pro Val Arg 965 970 975Cys Thr Cys Ser Ala Gln Gly Thr Gly Phe Ser Cys Pro Ser Ser 980 985 990Val Gly Gly His Pro Pro Gln Met Arg Val Val Thr Gly Asp Ile 995 10001005 Leu Thr Asp Ile Thr Gly His Asn Val Ser Glu Tyr Leu Leu Phe 10101015 1020 Thr Ser Asp Arg Phe Arg Leu His Arg Tyr Gly Ala Ile Thr Phe1025 1030 1035 Gly Asn Val Leu Lys Ser Ile Pro Ala Ser Phe Gly Thr ArgAla 1040 1045 1050 Pro Pro Met Val Arg Lys Ile Ala Val Arg Arg Ala AlaGln Val 1055 1060 1065 Phe Tyr Asn Asn Lys Gly Tyr His Ser Met Pro ThrTyr Leu Asn 1070 1075 1080 Ser Leu Asn Asn Ala Ile Leu Arg Ala Asn LeuPro Lys Ser Lys 1085 1090 1095 Gly Asn Pro Ala Ala Tyr Gly Ile Thr ValThr Asn His Pro Met 1100 1105 1110 Asn Lys Thr Ser Ala Ser Leu Ser LeuAsp Tyr Leu Leu Gln Gly 1115 1120 1125 Thr Asp Val Val Ile Ala Ile PheIle Ile Val Ala Met Ser Phe 1130 1135 1140 Val Pro Ala Ser Phe Val ValPhe Leu Val Ala Glu Lys Ser Thr 1145 1150 1155 Lys Ala Lys His Leu GlnPhe Val Ser Gly Cys Asn Pro Ile Ile 1160 1165 1170 Tyr Trp Leu Ala AsnTyr Val Trp Asp Met Leu Asn Tyr Leu Val 1175 1180 1185 Pro Ala Thr CysCys Val Ile Ile Leu Phe Val Phe Asp Leu Pro 1190 1195 1200 Ala Tyr ThrSer Pro Thr Asn Phe Pro Ala Val Leu Ser Leu Phe 1205 1210 1215 Leu LeuTyr Gly Trp Ser Ile Thr Pro Ile Met Tyr Pro Ala Ser 1220 1225 1230 PheTrp Phe Glu Val Pro Ser Ser Ala Tyr Val Phe Leu Ile Val 1235 1240 1245Ile Asn Leu Phe Ile Gly Ile Thr Ala Thr Val Ala Thr Phe Leu 1250 12551260 Leu Gln Leu Phe Glu His Asp Lys Asp Leu Lys Val Val Asn Ser 12651270 1275 Tyr Leu Lys Ser Cys Phe Leu Ile Phe Pro Asn Tyr Asn Leu Gly1280 1285 1290 His Gly Leu Met Glu Met Ala Tyr Asn Glu Tyr Ile Asn GluTyr 1295 1300 1305 Tyr Ala Lys Ile Gly Gln Phe Asp Lys Met Lys Ser ProPhe Glu 1310 1315 1320 Trp Asp Ile Val Thr Arg Gly Leu Val Ala Met AlaVal Glu Gly 1325 1330 1335 Val Val Gly Phe Leu Leu Thr Ile Met Cys GlnTyr Asn Phe Leu 1340 1345 1350 Arg Arg Pro Gln Arg Met Pro Val Ser ThrLys Pro Val Glu Asp 1355 1360 1365 Asp Val Asp Val Ala Ser Glu Arg GlnArg Val Leu Arg Gly Asp 1370 1375 1380 Ala Asp Asn Asp Met Val Lys IleGlu Asn Leu Thr Lys Val Tyr 1385 1390 1395 Lys Ser Arg Lys Ile Gly ArgIle Leu Ala Val Asp Arg Leu Cys 1400 1405 1410 Leu Gly Val Arg Pro GlyGlu Cys Phe Gly Leu Leu Gly Val Asn 1415 1420 1425 Gly Ala Gly Lys ThrSer Thr Phe Lys Met Leu Thr Gly Asp Glu 1430 1435 1440 Ser Thr Thr GlyGly Glu Ala Phe Val Asn Gly His Ser Val Leu 1445 1450 1455 Lys Glu LeuLeu Gln Val Gln Gln Ser Leu Gly Tyr Cys Pro Gln 1460 1465 1470 Cys AspAla Leu Phe Asp Glu Leu Thr Ala Arg Glu His Leu Gln 1475 1480 1485 LeuTyr Thr Arg Leu Arg Gly Ile Ser Trp Lys Asp Glu Ala Arg 1490 1495 1500Val Val Lys Trp Ala Leu Glu Lys Leu Glu Leu Thr Lys Tyr Ala 1505 15101515 Asp Lys Pro Ala Gly Thr Tyr Ser Gly Gly Asn Lys Arg Lys Leu 15201525 1530 Ser Thr Ala Ile Ala Leu Ile Gly Tyr Pro Ala Phe Ile Phe Leu1535 1540 1545 Asp Glu Pro Thr Thr Gly Met Asp Pro Lys Ala Arg Arg PheLeu 1550 1555 1560 Trp Asn Leu Ile Leu Asp Leu Ile Lys Thr Gly Arg SerVal Val 1565 1570 1575 Leu Thr Ser His Ser Met Glu Glu Cys Glu Ala LeuCys Thr Arg 1580 1585 1590 Leu Ala Ile Met Val Asn Gly Arg Leu Arg CysLeu Gly Ser Ile 1595 1600 1605 Gln His Leu Lys Asn Arg Phe Gly Asp GlyTyr Met Ile Thr Val 1610 1615 1620 Arg Thr Lys Ser Ser Gln Ser Val LysAsp Val Val Arg Phe Phe 1625 1630 1635 Asn Arg Asn Phe Pro Glu Ala MetLeu Lys Glu Arg His His Thr 1640 1645 1650 Lys Val Gln Tyr Gln Leu LysSer Glu His Ile Ser Leu Ala Gln 1655 1660 1665 Val Phe Ser Lys Met GluGln Val Ser Gly Val Leu Gly Ile Glu 1670 1675 1680 Asp Tyr Ser Val SerGln Thr Thr Leu Asp Asn Val Phe Val Asn 1685 1690 1695 Phe Ala Lys LysGln Ser Asp Asn Leu Glu Gln Gln Glu Thr Glu 1700 1705 1710 Pro Pro SerAla Leu Gln Ser Pro Leu Gly Cys Leu Leu Ser Leu 1715 1720 1725 Leu ArgPro Arg Ser Ala Pro Thr Glu Leu Arg Ala Leu Val Ala 1730 1735 1740 AspGlu Pro Glu Asp Leu Asp Thr Glu Asp Glu Gly Leu Ile Ser 1745 1750 1755Phe Glu Glu Glu Arg Ala Gln Leu Ser Phe Asn Thr Asp Thr Leu 1760 17651770 Cys 19 474 PRT Homo sapiens misc_feature Incyte ID No 7472537CD1 19Met Phe Ser Leu Ser Tyr Leu Cys Val Cys Val Phe Ser Gln Phe 1 5 10 15Ala Asn Glu Asp Thr Glu Ser Gln Lys Phe Leu Thr Asn Gly Phe 20 25 30 LeuGly Lys Lys Lys Leu Ala Asp Pro Phe Phe Phe Lys His Pro 35 40 45 Gly ThrThr Ser Phe Gly Met Ser Ser Phe Asn Leu Ser Asn Ala 50 55 60 Ile Met GlySer Gly Ile Leu Gly Leu Ser Tyr Ala Met Ala Asn 65 70 75 Thr Gly Ile IleLeu Phe Met Phe Met Leu Leu Ala Val Ala Ile 80 85 90 Leu Ser Leu Tyr SerVal His Leu Leu Leu Lys Thr Ser Leu Ile 95 100 105 Val Gly Ser Leu IleTyr Glu Lys Leu Gly Glu Lys Ala Phe Gly 110 115 120 Trp Pro Gly Lys IleGly Ala Phe Val Ser Ile Thr Met Gln Asn 125 130 135 Ile Gly Ala Met SerSer Tyr Leu Phe Ile Ile Lys Tyr Glu Leu 140 145 150 Pro Glu Val Ile ArgAla Phe Met Gly Leu Glu Glu Thr Ser Arg 155 160 165 Glu Trp Tyr Leu AsnGly Asn Tyr Leu Ile Ile Phe Val Ser Val 170 175 180 Gly Ile Ile Leu ProLeu Ser Leu Leu Lys Asn Leu Gly Tyr Leu 185 190 195 Gly Tyr Thr Ser GlyPhe Ser Leu Thr Cys Met Val Phe Phe Val 200 205 210 Ser Val Val Ile TyrLys Lys Phe Gln Ile Pro Cys Pro Leu Pro 215 220 225 Glu Asn Gln Ala LysGly Ser Leu His Asp Ser Gly Val Glu Tyr 230 235 240 Glu Ala His Ser AspAsp Lys Cys Glu Pro Lys Tyr Phe Val Phe 245 250 255 Asn Ser Gln Thr AlaTyr Ala Ile Pro Ile Leu Val Phe Ala Phe 260 265 270 Val Cys His Pro GluVal Leu Pro Ile Tyr Ser Glu Leu Lys Asp 275 280 285 Arg Ser Arg Arg LysMet Gln Thr Val Ser Asn Ile Ser Ile Thr 290 295 300 Gly Met Leu Val MetTyr Leu Leu Ala Ala Leu Phe Gly Tyr Leu 305 310 315 Thr Phe Tyr Gly ArgVal Glu Asp Glu Leu Leu His Ala Tyr Ser 320 325 330 Lys Val Tyr Thr LeuAsp Ile Pro Leu Leu Met Val Arg Leu Ala 335 340 345 Val Leu Val Ala ValThr Leu Thr Val Pro Ile Val Leu Phe Pro 350 355 360 Val Arg Thr Ser ValIle Thr Leu Leu Phe Pro Lys Arg Pro Phe 365 370 375 Ser Trp Ile Arg HisPhe Leu Ile Ala Ala Val Leu Ile Ala Leu 380 385 390 Asn Asn Val Leu ValIle Leu Val Pro Thr Ile Lys Tyr Ile Phe 395 400 405 Gly Phe Ile Gly AlaSer Ser Ala Thr Met Leu Ile Phe Ile Leu 410 415 420 Pro Ala Val Phe TyrLeu Lys Leu Val Lys Lys Glu Thr Phe Arg 425 430 435 Ser Pro Pro Glu LeuGln Ala Leu Ile Phe Leu Val Val Gly Ile 440 445 450 Phe Phe Met Ile GlySer Met Ala Leu Ile Ile Ile Asp Trp Ile 455 460 465 Tyr Asp Pro Pro AsnSer Lys His His 470 20 752 PRT Homo sapiens misc_feature Incyte ID No7472546CD1 20 Met Glu Tyr Gln Ala Ser Glu Val Ile Gly Gln Arg Gln SerSer 1 5 10 15 Ala Thr Lys Pro Gly Arg Ser Gly Lys Glu Ser Val Thr GluPro 20 25 30 Trp Ala Arg Val Pro Gly Ala Leu Gly Val Ala Ala Arg Gln Met35 40 45 His Pro Lys Ser Ile Ile Thr Phe Arg Glu Ile Asn Gly Glu Tyr 5055 60 Thr Gly Ala Val Asp Phe Pro Arg Leu Gly Val Arg Ala Ser Glu 65 7075 Glu Thr Ala Leu Arg Glu Leu Lys Met Ser Lys Glu Leu Ala Ala 80 85 90Met Gly Pro Gly Ala Ser Gly Asp Gly Val Arg Thr Glu Thr Ala 95 100 105Pro His Ile Ala Leu Asp Ser Arg Val Gly Leu His Ala Tyr Asp 110 115 120Ile Ser Val Val Val Ile Tyr Phe Val Phe Val Ile Ala Val Gly 125 130 135Ile Trp Ser Ser Ile Arg Ala Ser Arg Gly Thr Ile Gly Gly Tyr 140 145 150Phe Leu Ala Gly Arg Ser Met Ser Trp Trp Pro Ile Gly Ala Ser 155 160 165Leu Met Ser Ser Asn Val Gly Ser Gly Leu Phe Ile Gly Leu Ala 170 175 180Gly Thr Gly Ala Ala Gly Gly Leu Ala Val Gly Gly Phe Glu Trp 185 190 195Asn Ala Thr Trp Leu Leu Leu Ala Leu Gly Trp Val Phe Val Pro 200 205 210Val Tyr Ile Ala Ala Gly Val Val Thr Met Pro Gln Tyr Leu Lys 215 220 225Lys Arg Phe Gly Gly Gln Arg Ile Gln Val Tyr Met Ser Val Leu 230 235 240Ser Leu Ile Leu Tyr Ile Phe Thr Lys Ile Ser Thr Asp Ile Phe 245 250 255Ser Gly Ala Leu Phe Ile Gln Met Ala Leu Gly Trp Asn Leu Tyr 260 265 270Leu Ser Thr Gly Ile Leu Leu Val Val Thr Ala Val Tyr Thr Ile 275 280 285Ala Gly Gly Leu Met Ala Val Ile Tyr Thr Asp Ala Leu Gln Thr 290 295 300Val Ile Met Val Gly Gly Ala Leu Val Leu Met Phe Leu Gly Phe 305 310 315Gln Asp Val Gly Trp Tyr Pro Gly Leu Glu Gln Arg Tyr Arg Gln 320 325 330Ala Ile Pro Asn Val Thr Val Pro Asn Thr Thr Cys His Leu Pro 335 340 345Arg Pro Asp Ala Phe His Ile Leu Arg Asp Pro Val Ser Gly Asp 350 355 360Ile Pro Trp Pro Gly Leu Ile Phe Gly Leu Thr Val Leu Ala Thr 365 370 375Trp Cys Trp Cys Thr Asp Gln Val Ile Val Gln Arg Ser Leu Ser 380 385 390Ala Lys Ser Leu Ser His Ala Lys Gly Gly Ser Val Leu Gly Gly 395 400 405Tyr Leu Lys Ile Leu Pro Met Phe Phe Ile Val Met Pro Gly Met 410 415 420Ile Ser Arg Ala Leu Phe Pro Asp Glu Val Gly Cys Val Asp Pro 425 430 435Asp Val Cys Gln Arg Ile Cys Gly Ala Arg Val Gly Cys Ser Asn 440 445 450Ile Ala Tyr Pro Lys Leu Val Met Ala Leu Met Pro Val Gly Leu 455 460 465Arg Gly Leu Met Ile Ala Val Ile Met Ala Ala Leu Met Ser Ser 470 475 480Leu Thr Ser Ile Phe Asn Ser Ser Ser Thr Leu Phe Thr Ile Asp 485 490 495Val Trp Gln Arg Phe Arg Arg Lys Ser Thr Glu Gln Glu Leu Met 500 505 510Val Val Gly Arg Val Phe Val Val Phe Leu Val Val Ile Ser Ile 515 520 525Leu Trp Ile Pro Ile Ile Gln Ser Ser Asn Ser Gly Gln Leu Phe 530 535 540Asp Tyr Ile Gln Ala Val Thr Ser Tyr Leu Ala Pro Pro Ile Thr 545 550 555Ala Leu Phe Leu Leu Ala Ile Phe Cys Lys Arg Val Thr Glu Pro 560 565 570Gly Ala Phe Trp Gly Leu Val Phe Gly Leu Gly Val Gly Leu Leu 575 580 585Arg Met Ile Leu Glu Phe Ser Tyr Pro Ala Pro Ala Cys Gly Glu 590 595 600Val Asp Arg Arg Pro Ala Val Leu Lys Asp Phe His Tyr Leu Tyr 605 610 615Phe Ala Ile Leu Leu Cys Gly Leu Thr Ala Ile Val Ile Val Ile 620 625 630Leu Thr Arg Leu Thr Trp Trp Thr Arg Asn Cys Pro Leu Ser Glu 635 640 645Leu Glu Lys Glu Ala His Glu Ser Thr Pro Glu Ile Ser Glu Arg 650 655 660Pro Ala Gly Glu Cys Pro Ala Gly Gly Gly Ala Ala Glu Asn Ser 665 670 675Ser Leu Gly Gln Glu Gln Pro Glu Ala Pro Ser Arg Ser Trp Gly 680 685 690Lys Leu Leu Trp Ser Trp Phe Cys Gly Leu Ser Gly Thr Pro Glu 695 700 705Gln Ala Leu Ser Pro Ala Glu Lys Ala Ala Leu Glu Gln Lys Leu 710 715 720Thr Ser Ile Glu Glu Glu Pro Leu Trp Arg His Val Cys Asn Ile 725 730 735Asn Ala Val Leu Leu Leu Ala Ile Asn Ile Phe Leu Trp Gly Tyr 740 745 750Phe Ala 21 654 PRT Homo sapiens misc_feature Incyte ID No 7474202CD1 21Met Glu Glu Leu Val Gly Leu Arg Glu Gly Phe Ser Gly Asp Pro 1 5 10 15Val Thr Leu Gln Glu Leu Trp Gly Pro Cys Pro His Ile Arg Arg 20 25 30 AlaIle Gln Gly Gly Leu Glu Trp Leu Lys Gln Lys Val Phe Arg 35 40 45 Leu GlyGlu Asp Trp Tyr Phe Leu Met Thr Leu Gly Val Leu Met 50 55 60 Ala Leu ValSer Tyr Ala Met Asn Phe Ala Ile Gly Cys Val Val 65 70 75 Arg Gly Phe SerGln Ser Ile Thr Pro Ser Ser Gly Gly Ser Gly 80 85 90 Ile Pro Glu Leu LysThr Met Leu Ala Gly Val Ile Leu Glu Asp 95 100 105 Tyr Leu Asp Ile LysAsn Phe Gly Ala Lys Val Val Gly Leu Ser 110 115 120 Cys Thr Leu Ala ThrGly Ser Thr Leu Phe Leu Gly Lys Val Gly 125 130 135 Pro Phe Val His LeuSer Val Met Ile Ala Ala Tyr Leu Gly Arg 140 145 150 Val Arg Thr Thr ThrIle Gly Glu Pro Glu Asn Lys Ser Lys Gln 155 160 165 Asn Glu Met Leu ValAla Ala Ala Ala Val Gly Val Ala Thr Val 170 175 180 Phe Ala Ala Pro PheSer Gly Val Leu Phe Ser Ile Glu Val Met 185 190 195 Ser Ser His Phe SerVal Arg Asp Tyr Trp Arg Gly Phe Phe Ala 200 205 210 Ala Thr Cys Gly AlaPhe Ile Phe Arg Leu Leu Ala Val Phe Asn 215 220 225 Ser Glu Gln Glu ThrIle Thr Ser Leu Tyr Lys Thr Ser Phe Arg 230 235 240 Val Asp Val Pro PheAsp Leu Pro Glu Ile Phe Phe Phe Val Ala 245 250 255 Leu Gly Gly Ile CysGly Val Leu Ser Cys Ala Tyr Leu Phe Cys 260 265 270 Gln Arg Thr Phe LeuSer Phe Ile Lys Thr Asn Arg Tyr Ser Ser 275 280 285 Lys Leu Leu Ala ThrSer Lys Pro Val Tyr Ser Ala Leu Ala Thr 290 295 300 Leu Leu Leu Ala SerIle Thr Tyr Pro Pro Gly Val Gly His Phe 305 310 315 Leu Ala Ser Arg LeuSer Met Lys Gln His Leu Asp Ser Leu Phe 320 325 330 Asp Asn His Ser TrpAla Leu Met Thr Gln Asn Ser Ser Pro Pro 335 340 345 Trp Pro Glu Glu LeuAsp Pro Gln His Leu Trp Trp Glu Trp Tyr 350 355 360 His Pro Arg Phe ThrIle Phe Gly Thr Leu Ala Phe Phe Leu Val 365 370 375 Met Lys Phe Trp MetLeu Ile Leu Ala Thr Thr Ile Pro Met Pro 380 385 390 Ala Gly Tyr Phe MetPro Ile Phe Ile Leu Gly Ala Ala Ile Gly 395 400 405 Arg Leu Leu Gly GluAla Leu Ala Val Ala Phe Pro Glu Gly Ile 410 415 420 Val Thr Gly Gly ValThr Asn Pro Ile Met Pro Gly Gly Tyr Ala 425 430 435 Leu Ala Gly Ala AlaAla Phe Ser Gly Ala Val Thr His Thr Ile 440 445 450 Ser Thr Ala Leu LeuAla Phe Glu Leu Thr Gly Gln Ile Val His 455 460 465 Ala Leu Pro Val LeuMet Ala Val Leu Ala Ala Asn Ala Ile Ala 470 475 480 Gln Ser Cys Gln ProSer Phe Tyr Asp Gly Thr Ile Ile Val Lys 485 490 495 Lys Leu Pro Tyr LeuPro Arg Ile Leu Gly Arg Asn Ile Gly Ser 500 505 510 His His Val Arg ValGlu His Phe Met Asn His Ser Ile Thr Thr 515 520 525 Leu Ala Lys Asp ThrPro Leu Glu Glu Val Val Lys Val Val Thr 530 535 540 Ser Thr Asp Val ThrGlu Tyr Pro Leu Val Glu Ser Thr Glu Ser 545 550 555 Gln Ile Leu Val GlyIle Val Gln Arg Ala Gln Leu Val Gln Ala 560 565 570 Leu Gln Ala Glu ProPro Ser Arg Ala Pro Gly His Gln Cys Leu 575 580 585 Gln Asp Ile Leu AlaArg Gly Cys Pro Thr Glu Pro Val Thr Leu 590 595 600 Thr Leu Phe Ser GluThr Thr Leu His Gln Ala Gln Asn Leu Phe 605 610 615 Lys Leu Leu Asn LeuGln Ser Leu Phe Val Thr Ser Arg Gly Arg 620 625 630 Ala Val Gly Cys ValSer Trp Val Glu Met Lys Lys Ala Ile Ser 635 640 645 Asn Leu Thr Asn ProPro Ala Pro Lys 650 22 886 PRT Homo sapiens misc_feature Incyte ID No7476280CD1 22 Met Asp Pro Ile Thr Pro Asn Trp Thr Glu Ile Val Asn ArgLys 1 5 10 15 Leu Ser Phe Pro Pro Pro Leu Leu Asp Ala Ile Gln Glu GlyArg 20 25 30 Leu Gly Phe Val Gln Gln Leu Leu Glu Ser Glu Val Glu Ala Ala35 40 45 Ser Ser Gly Pro Gly Trp Pro Leu Trp Asn Val Glu Glu Ala Glu 5055 60 Asp Arg Cys Trp Arg Glu Ala Leu Asn Leu Ala Ile Arg Leu Gly 65 7075 His Glu Ala Leu Thr Asp Val Leu Leu Ala Ser Val Lys Phe Asp 80 85 90Phe Arg Gln Ile His Glu Ala Leu Leu Val Ala Val Asp Thr Asn 95 100 105Gln Ala Val Val Arg Arg Leu Pro Ala Arg Leu Glu Arg Glu Lys 110 115 120Gly Arg Lys Val Asp Thr Arg Ser Phe Ser Leu Ala Phe Phe Asp 125 130 135Ser Ser Ile Asp Gly Ser Arg Phe Ala Pro Gly Val Thr Pro Leu 140 145 150Pro Gln Ala Cys Gln Lys Asp Leu Tyr Glu Ile Ala Gln Leu Leu 155 160 165Met Glu Gln Gly His Thr Ile Ala Arg Pro His Pro Val Ser Cys 170 175 180Ala Cys Leu Glu Cys Ser Asn Ala Arg Arg Tyr Asp Leu Leu Lys 185 190 195Leu Ser Leu Ser Arg Ile Asn Thr Tyr Leu Gly Ile Ala Ser Arg 200 205 210Ala His Leu Ser Leu Ala Ser Glu Asp Ala Met Leu Ala Ala Phe 215 220 225Gln Leu Ser Arg Glu Leu Arg Arg Leu Ala Arg Lys Glu Pro Glu 230 235 240Phe Lys Pro Glu Tyr Ile Ala Leu Glu Ser Leu Ser Gln Asp Tyr 245 250 255Gly Phe Gln Leu Leu Gly Met Cys Trp Asn Gln Ser Glu Val Thr 260 265 270Ala Val Leu Asn Asp Leu Ala Glu Asp Ser Glu Thr Glu Pro Glu 275 280 285Ala Glu Gly Leu Gly Leu Ala Phe Glu Glu Gly Ile Pro Asn Leu 290 295 300Val Arg Leu Arg Leu Ala Val Asn Tyr Asn Gln Lys Arg Phe Val 305 310 315Ala His Leu Ile Cys Gln Gln Val Leu Ser Ser Ile Trp Cys Gly 320 325 330Asn Leu Ala Gly Trp Arg Gly Ser Thr Thr Ser Trp Lys Leu Phe 335 340 345Ala Thr Phe Leu Ile Phe Leu Thr Met Pro Phe Leu Cys Leu Gly 350 355 360Tyr Trp Leu Thr Pro Lys Ser Gln Leu Gly His Leu Leu Lys Ile 365 370 375Pro Val Leu Lys Phe Leu Leu His Ser Ala Ser Tyr Leu Trp Phe 380 385 390Leu Ile Phe Leu Leu Gly Glu Ser Leu Val Met Glu Thr Gln Leu 395 400 405Ser Thr Phe Arg Gly Arg Ser Gln Ser Val Trp Glu Thr Ser Leu 410 415 420His Met Ile Cys Val Thr Gly Phe Leu Trp Phe Glu Cys Lys Glu 425 430 435Val Trp Ile Glu Gly Leu Arg Ser Tyr Leu Leu Asp Trp Trp Asn 440 445 450Phe Leu Asp Met Val Val Leu Ser Leu Tyr Leu Ala Ala Phe Ala 455 460 465Leu Arg Leu Leu Leu Ala Gly Leu Ala Pro Met His Cys Arg Asp 470 475 480Ala Ser Gln Ala Ala Ala Cys His Tyr Phe Thr Met Ala Glu Arg 485 490 495Ser Glu Trp His Thr Glu Asp Pro Gln Phe Leu Ala Glu Val Leu 500 505 510Phe Thr Ala Thr Ser Met Leu Ser Phe Thr Arg Leu Ala Tyr Ile 515 520 525Leu Pro Ala His Glu Ser Leu Gly Thr Leu Gln Ile Ser Ile Gly 530 535 540Lys Met Ile Glu Asp Met Ile Arg Phe Met Phe Ile Leu Met Ile 545 550 555Ile Leu Thr Ala Phe Leu Cys Gly Leu Asn Asn Ile Tyr Val Pro 560 565 570Tyr Gln Lys Thr Glu Trp Leu Gly Lys Ser Phe Asn Glu Thr Phe 575 580 585Gln Phe Leu Phe Trp Thr Met Phe Gly Met Glu Glu His Ser Val 590 595 600Val Asp Val Pro Gln Phe Leu Val Pro Glu Phe Ala Gly Arg Ala 605 610 615Leu Tyr Gly Ile Phe Thr Ile Ile Met Val Ile Val Leu Leu Asn 620 625 630Met Leu Ile Ala Met Ile Thr Asn Ser Phe Gln Lys Ile Glu Asp 635 640 645Asp Ala Asp Val Glu Trp Thr Phe Ala Arg Ser Lys Leu Tyr Leu 650 655 660Phe Tyr Phe Arg Glu Gly Leu Thr Leu Pro Val Pro Phe Asn Ile 665 670 675Leu Pro Ser Ser Lys Ala Val Phe Tyr Leu Leu Arg Arg Ile Cys 680 685 690Gln Phe Ile Cys Cys Cys Cys Ser Cys Cys Lys Thr Lys Lys Pro 695 700 705Asp Tyr Pro Pro Ile Pro Thr Phe Val Asn Pro Arg Ala Gly Ala 710 715 720Val Pro Gly Glu Gly Glu Arg Gly Ser Tyr Arg Leu His Val Ile 725 730 735Lys Ala Leu Val Gln Arg Tyr Thr Glu Thr Ala Arg Arg Glu Phe 740 745 750Glu Glu Thr Arg Arg Lys Asp Leu Gly Asn Arg Leu Thr Glu Leu 755 760 765Thr Lys Thr Ile Ser Arg Leu Gln Ser Glu Val Ala Gly Val Arg 770 775 780Arg Thr Leu Ala Glu Gly Gly Thr Pro Arg Pro Pro Asp Gly Ala 785 790 795Ser Val Leu Ser His Tyr Ile Thr Gln Val His Asn Ser Phe Gln 800 805 810Asn Leu Gly Pro Pro Ile Pro Glu Thr Pro Glu Leu Thr Gly Pro 815 820 825Gly Ile Val Arg Thr Gln Glu Ser Ser Gly Thr Gly Leu Gln Asp 830 835 840Thr Gly Gly Val Arg Thr Leu Ala Ser Gly Glu Ser Gly Pro Cys 845 850 855Ser Pro Ala His Val Leu Val His Arg Glu Gln Glu Ala Glu Gly 860 865 870Ala Gly Asp Leu Pro Gln Gly Glu Asp Ser Gly Thr Glu Arg Arg 875 880 885Ser 23 512 PRT Homo sapiens misc_feature Incyte ID No 1713377CD1 23 MetAla Gly Gly Met Ser Ala Glu Cys Pro Glu Pro Gly Pro Gly 1 5 10 15 GlyLeu Gln Gly Gln Ser Pro Gly Pro Gly Arg Gln Cys Pro Pro 20 25 30 Pro IleThr Pro Thr Ser Trp Ser Leu Pro Pro Trp Arg Ala Tyr 35 40 45 Val Ala AlaAla Val Leu Cys Tyr Ile Asn Leu Leu Asn Tyr Met 50 55 60 Asn Trp Phe IleIle Ala Gly Val Leu Leu Asp Ile Gln Glu Val 65 70 75 Phe Gln Ile Ser AspAsn His Ala Gly Leu Leu Gln Thr Val Phe 80 85 90 Val Ser Cys Leu Leu LeuSer Ala Pro Val Phe Gly Tyr Leu Gly 95 100 105 Asp Arg His Ser Arg LysAla Thr Met Ser Phe Gly Ile Leu Leu 110 115 120 Trp Ser Gly Ala Gly LeuSer Ser Ser Phe Ile Ser Pro Arg Tyr 125 130 135 Ser Trp Leu Phe Phe LeuSer Arg Gly Ile Val Gly Thr Gly Ser 140 145 150 Ala Ser Tyr Ser Thr IleAla Pro Thr Val Leu Gly Asp Leu Phe 155 160 165 Val Arg Asp Gln Arg ThrArg Val Leu Ala Val Phe Tyr Ile Phe 170 175 180 Ile Pro Val Gly Ser GlyLeu Gly Tyr Val Leu Gly Ser Ala Val 185 190 195 Thr Met Leu Thr Gly AsnTrp Arg Trp Ala Leu Arg Val Met Pro 200 205 210 Cys Leu Glu Ala Val AlaLeu Ile Leu Leu Ile Leu Leu Val Pro 215 220 225 Asp Pro Pro Arg Gly AlaAla Glu Thr Gln Gly Glu Gly Ala Val 230 235 240 Gly Gly Phe Arg Ser SerTrp Cys Glu Asp Val Arg Tyr Leu Gly 245 250 255 Lys Asn Trp Ser Phe ValTrp Ser Thr Leu Gly Val Thr Ala Met 260 265 270 Ala Phe Val Thr Gly AlaLeu Gly Phe Trp Ala Pro Lys Phe Leu 275 280 285 Leu Glu Ala Arg Val ValHis Gly Leu Gln Pro Pro Cys Phe Gln 290 295 300 Glu Pro Cys Ser Asn ProAsp Ser Leu Ile Phe Gly Ala Leu Thr 305 310 315 Ile Met Thr Gly Val IleGly Val Ile Leu Gly Ala Glu Ala Ser 320 325 330 Arg Arg Tyr Lys Lys ValIle Pro Gly Ala Glu Pro Leu Ile Cys 335 340 345 Ala Ser Ser Leu Leu AlaThr Ala Pro Cys Leu Tyr Leu Ala Leu 350 355 360 Val Leu Ala Pro Thr ThrLeu Leu Ala Ser Tyr Val Phe Leu Gly 365 370 375 Leu Gly Glu Leu Leu LeuSer Cys Asn Trp Ala Val Val Ala Asp 380 385 390 Ile Leu Leu Ser Val ValVal Pro Arg Cys Arg Gly Thr Ala Glu 395 400 405 Ala Leu Gln Ile Thr ValGly His Ile Leu Gly Asp Ala Gly Ser 410 415 420 Pro Tyr Leu Thr Gly LeuIle Ser Ser Val Leu Arg Ala Arg Arg 425 430 435 Pro Asp Ser Tyr Leu GlnArg Phe Arg Ser Leu Gln Gln Ser Phe 440 445 450 Leu Cys Cys Ala Phe ValIle Ala Leu Gly Gly Gly Cys Phe Leu 455 460 465 Leu Thr Ala Leu Tyr LeuGlu Arg Asp Glu Thr Arg Ala Trp Gln 470 475 480 Pro Val Thr Gly Thr ProAsp Ser Asn Asp Val Asp Ser Asn Asp 485 490 495 Leu Glu Arg Gln Gly LeuLeu Ser Gly Ala Gly Ala Ser Thr Glu 500 505 510 Glu Pro 24 475 PRT Homosapiens misc_feature Incyte ID No 5842557CD1 24 Met Ile Pro Ala Tyr SerLys Asn Arg Ala Tyr Ala Ile Phe Phe 1 5 10 15 Ile Val Phe Thr Val IleGly Ser Leu Phe Leu Met Asn Leu Leu 20 25 30 Thr Ala Ile Ile Tyr Ser GlnPhe Arg Gly Tyr Leu Met Lys Ser 35 40 45 Leu Gln Thr Ser Leu Phe Arg ArgArg Leu Gly Thr Arg Ala Ala 50 55 60 Phe Glu Val Leu Ser Ser Met Val GlyGlu Gly Gly Ala Phe Pro 65 70 75 Gln Ala Val Gly Val Lys Pro Gln Asn LeuLeu Gln Val Leu Gln 80 85 90 Lys Val Gln Leu Asp Ser Ser His Lys Gln AlaMet Met Glu Lys 95 100 105 Val Arg Ser Tyr Asp Ser Val Leu Leu Ser AlaGlu Glu Phe Gln 110 115 120 Lys Leu Phe Asn Glu Leu Asp Arg Ser Val ValLys Glu His Pro 125 130 135 Pro Arg Pro Glu Tyr Gln Ser Pro Phe Leu GlnSer Ala Gln Phe 140 145 150 Leu Phe Gly His Tyr Tyr Phe Asp Tyr Leu GlyAsn Leu Ile Ala 155 160 165 Leu Ala Asn Leu Val Ser Ile Cys Val Phe LeuVal Leu Asp Ala 170 175 180 Asp Val Leu Pro Ala Glu Arg Asp Asp Phe IleLeu Gly Ile Leu 185 190 195 Asn Cys Val Phe Ile Val Tyr Tyr Leu Leu GluMet Leu Leu Lys 200 205 210 Val Phe Ala Leu Gly Leu Arg Gly Tyr Leu SerTyr Pro Ser Asn 215 220 225 Val Phe Asp Gly Leu Leu Thr Val Val Leu LeuVal Leu Glu Ile 230 235 240 Ser Thr Leu Ala Val Tyr Arg Leu Pro His ProGly Trp Arg Pro 245 250 255 Glu Met Val Gly Leu Leu Ser Leu Trp Asp MetThr Arg Met Leu 260 265 270 Asn Met Leu Ile Val Phe Arg Phe Leu Arg IleIle Pro Ser Met 275 280 285 Lys Pro Met Ala Val Val Ala Ser Thr Val LeuGly Leu Val Gln 290 295 300 Asn Met Arg Ala Phe Gly Gly Ile Leu Val ValVal Tyr Tyr Val 305 310 315 Phe Ala Ile Ile Gly Ile Asn Leu Phe Arg GlyVal Ile Val Ala 320 325 330 Leu Pro Gly Asn Ser Ser Leu Ala Pro Ala AsnGly Ser Ala Pro 335 340 345 Cys Gly Ser Phe Glu Gln Leu Glu Tyr Trp AlaAsn Asn Phe Asp 350 355 360 Asp Phe Ala Ala Ala Leu Val Thr Leu Trp AsnLeu Met Val Val 365 370 375 Asn Asn Trp Gln Val Phe Leu Asp Ala Tyr ArgArg Tyr Ser Gly 380 385 390 Pro Trp Ser Lys Ile Tyr Phe Val Leu Trp TrpLeu Val Ser Ser 395 400 405 Val Ile Trp Val Asn Leu Phe Leu Ala Leu IleLeu Glu Asn Phe 410 415 420 Leu His Lys Trp Asp Pro Arg Ser His Leu GlnPro Leu Ala Gly 425 430 435 Thr Pro Glu Ala Thr Tyr Gln Met Thr Val GluLeu Leu Phe Arg 440 445 450 Asp Ile Leu Glu Glu Pro Glu Glu Asp Glu LeuThr Glu Arg Leu 455 460 465 Ser Gln His Pro His Leu Trp Leu Cys Arg 470475 25 537 PRT Homo sapiens misc_feature Incyte ID No 7476643CD1 25 MetAla Arg Lys Gln Asn Arg Asn Ser Lys Glu Leu Gly Leu Val 1 5 10 15 ProLeu Thr Asp Asp Thr Ser His Ala Arg Pro Pro Gly Pro Gly 20 25 30 Arg AlaLeu Leu Glu Cys Asp His Leu Arg Ser Gly Val Pro Gly 35 40 45 Gly Arg ArgArg Lys Asp Trp Ser Cys Ser Leu Leu Val Ala Ser 50 55 60 Leu Ala Gly AlaPhe Gly Ser Ser Phe Leu Tyr Gly Tyr Asn Leu 65 70 75 Ser Val Val Asn AlaPro Thr Pro Tyr Ile Lys Ala Phe Tyr Asn 80 85 90 Glu Ser Trp Glu Arg ArgHis Gly Arg Pro Ile Asp Pro Asp Thr 95 100 105 Leu Thr Leu Leu Trp SerVal Thr Val Ser Ile Phe Ala Ile Gly 110 115 120 Gly Leu Val Gly Thr LeuIle Val Lys Met Ile Gly Lys Val Leu 125 130 135 Gly Arg Lys His Thr LeuLeu Ala Asn Asn Gly Phe Ala Ile Ser 140 145 150 Ala Ala Leu Leu Met AlaCys Ser Leu Gln Ala Gly Ala Phe Glu 155 160 165 Met Leu Ile Val Gly ArgPhe Ile Met Gly Ile Asp Gly Gly Val 170 175 180 Ala Leu Ser Val Leu ProMet Tyr Leu Ser Glu Ile Ser Pro Lys 185 190 195 Glu Ile Arg Gly Ser LeuGly Gln Val Thr Ala Ile Phe Ile Cys 200 205 210 Ile Gly Val Phe Thr GlyGln Leu Leu Gly Leu Pro Glu Leu Leu 215 220 225 Gly Lys Glu Ser Thr TrpPro Tyr Leu Phe Gly Val Ile Val Val 230 235 240 Pro Ala Val Val Gln LeuLeu Ser Leu Pro Phe Leu Pro Asp Ser 245 250 255 Pro Arg Tyr Leu Leu LeuGlu Lys His Asn Glu Ala Arg Ala Val 260 265 270 Lys Ala Phe Gln Thr PheLeu Gly Lys Ala Asp Val Ser Gln Glu 275 280 285 Val Glu Glu Val Leu AlaGlu Ser Arg Val Gln Arg Ser Ile Arg 290 295 300 Leu Val Ser Val Leu GluLeu Leu Arg Ala Pro Tyr Val Arg Trp 305 310 315 Gln Val Val Thr Val IleVal Thr Met Ala Cys Tyr Gln Leu Cys 320 325 330 Gly Leu Asn Ala Ile TrpPhe Tyr Thr Asn Ser Ile Phe Gly Lys 335 340 345 Ala Gly Ile Pro Leu AlaLys Ile Pro Tyr Val Thr Leu Ser Thr 350 355 360 Gly Gly Ile Glu Thr LeuAla Ala Val Phe Ser Gly Leu Val Ile 365 370 375 Glu His Leu Gly Arg ArgPro Leu Leu Ile Gly Gly Phe Gly Leu 380 385 390 Met Gly Leu Phe Phe GlyThr Leu Thr Ile Thr Leu Thr Leu Gln 395 400 405 Asp His Ala Pro Trp ValPro Tyr Leu Ser Ile Val Gly Ile Leu 410 415 420 Ala Ile Ile Ala Ser PheCys Ser Gly Pro Gly Gly Ile Pro Phe 425 430 435 Ile Leu Thr Gly Glu PhePhe Gln Gln Ser Gln Arg Pro Ala Ala 440 445 450 Phe Ile Ile Ala Gly ThrVal Asn Trp Leu Ser Asn Phe Ala Val 455 460 465 Gly Leu Leu Phe Pro PheIle Gln Lys Ser Leu Asp Thr Tyr Cys 470 475 480 Phe Leu Val Phe Ala ThrIle Cys Ile Thr Gly Ala Ile Tyr Leu 485 490 495 Tyr Phe Val Leu Pro GluThr Lys Asn Arg Thr Tyr Ala Glu Ile 500 505 510 Ser Gln Ala Phe Ser LysArg Asn Lys Ala Tyr Pro Pro Glu Glu 515 520 525 Lys Ile Asp Ser Ala ValThr Asp Ala Gln Arg Asn 530 535 26 905 PRT Homo sapiens misc_featureIncyte ID No 7611651CD1 26 Met Pro Val Arg Arg Gly His Val Ala Pro GlnAsn Thr Tyr Leu 1 5 10 15 Asp Thr Ile Ile Arg Lys Phe Glu Gly Gln SerArg Lys Phe Leu 20 25 30 Ile Ala Asn Ala Gln Met Glu Asn Cys Ala Ile IleTyr Cys Asn 35 40 45 Asp Gly Phe Cys Glu Leu Phe Gly Tyr Ser Arg Val GluVal Met 50 55 60 Gln Gln Pro Cys Thr Cys Asp Phe Leu Thr Gly Pro Asn ThrPro 65 70 75 Ser Ser Ala Val Ser Arg Leu Ala Gln Ala Leu Leu Gly Ala Glu80 85 90 Glu Cys Lys Val Asp Ile Leu Tyr Tyr Arg Lys Asp Ala Ser Ser 95100 105 Phe Arg Cys Leu Val Asp Val Val Pro Val Lys Asn Glu Asp Gly 110115 120 Ala Val Ile Met Phe Ile Leu Asn Phe Glu Asp Leu Ala Gln Leu 125130 135 Leu Ala Lys Cys Ser Ser Arg Ser Leu Ser Gln Arg Leu Leu Ser 140145 150 Gln Ser Phe Leu Gly Ser Glu Gly Ser His Gly Arg Pro Gly Gly 155160 165 Pro Gly Pro Gly Thr Gly Arg Gly Lys Tyr Arg Thr Ile Ser Gln 170175 180 Ile Pro Gln Phe Thr Leu Asn Phe Val Glu Phe Asn Leu Glu Lys 185190 195 His Arg Ser Ser Ser Thr Thr Glu Ile Glu Ile Ile Ala Pro His 200205 210 Lys Val Val Glu Arg Thr Gln Asn Val Thr Glu Lys Val Thr Gln 215220 225 Val Leu Ser Leu Gly Ala Asp Val Leu Pro Glu Tyr Lys Leu Gln 230235 240 Ala Pro Arg Ile His Arg Trp Thr Ile Leu His Tyr Ser Pro Phe 245250 255 Lys Ala Val Trp Asp Trp Leu Ile Leu Leu Leu Val Ile Tyr Thr 260265 270 Ala Val Phe Thr Pro Tyr Ser Ala Ala Phe Leu Leu Ser Asp Gln 275280 285 Asp Glu Ser Arg Arg Gly Ala Cys Ser Tyr Thr Cys Ser Pro Leu 290295 300 Thr Val Val Asp Leu Ile Val Asp Ile Met Phe Val Val Asp Ile 305310 315 Val Ile Asn Phe Arg Thr Thr Tyr Val Asn Thr Asn Asp Glu Val 320325 330 Val Ser His Pro Arg Arg Ile Ala Val His Tyr Phe Lys Gly Trp 335340 345 Phe Leu Ile Asp Met Val Ala Ala Ile Pro Phe Asp Leu Leu Ile 350355 360 Phe Arg Thr Gly Ser Asp Glu Thr Thr Thr Leu Ile Gly Leu Leu 365370 375 Lys Thr Ala Arg Leu Leu Arg Leu Val Arg Val Ala Arg Lys Leu 380385 390 Asp Arg Tyr Ser Glu Tyr Gly Ala Ala Val Leu Phe Leu Leu Met 395400 405 Cys Thr Phe Ala Leu Ile Ala His Trp Leu Ala Cys Ile Cys Ser 410415 420 Leu Thr Ser Val Gly Phe Gly Asn Val Ser Pro Asn Thr Asn Ser 425430 435 Glu Lys Val Phe Ser Ile Cys Val Met Leu Ile Gly Ser Leu Met 440445 450 Tyr Ala Ser Ile Phe Gly Asn Val Ser Ala Ile Ile Gln Arg Leu 455460 465 Tyr Ser Gly Thr Ala Arg Tyr His Thr Gln Met Leu Arg Val Lys 470475 480 Glu Phe Ile Arg Phe His Gln Ile Pro Asn Pro Leu Arg Gln Arg 485490 495 Leu Glu Glu Tyr Phe Gln His Ala Trp Ser Tyr Thr Asn Gly Ile 500505 510 Asp Met Asn Ala Val Leu Lys Gly Phe Pro Glu Cys Leu Gln Ala 515520 525 Asp Ile Cys Leu His Leu His Arg Ala Leu Leu Gln His Cys Pro 530535 540 Ala Phe Ser Gly Ala Gly Lys Gly Cys Leu Arg Ala Leu Ala Val 545550 555 Lys Phe Lys Thr Thr His Ala Pro Pro Gly Asp Thr Leu Val His 560565 570 Leu Gly Asp Val Leu Ser Thr Leu Tyr Phe Ile Ser Arg Gly Ser 575580 585 Ile Glu Ile Leu Arg Asp Asp Val Val Val Ala Ile Leu Gly Lys 590595 600 Asn Asp Ile Phe Gly Glu Pro Val Ser Leu His Ala Gln Pro Gly 605610 615 Lys Ser Ser Ala Asp Val Arg Ala Leu Thr Tyr Cys Asp Leu His 620625 630 Lys Ile Gln Arg Ala Asp Leu Leu Glu Val Leu Asp Met Tyr Pro 635640 645 Ala Phe Ala Glu Ser Phe Trp Ser Lys Leu Glu Val Thr Phe Asn 650655 660 Leu Arg Asp Ala Ala Gly Gly Leu His Ser Ser Pro Arg Gln Ala 665670 675 Pro Gly Ser Gln Asp His Gln Gly Phe Phe Leu Ser Asp Asn Gln 680685 690 Ser Asp Ala Ala Pro Pro Leu Ser Ile Ser Asp Ala Ser Gly Leu 695700 705 Trp Pro Glu Leu Leu Gln Glu Met Pro Pro Arg His Ser Pro Gln 710715 720 Ser Pro Gln Glu Asp Pro Asp Cys Trp Pro Leu Lys Leu Gly Ser 725730 735 Arg Leu Glu Gln Leu Gln Ala Gln Met Asn Arg Leu Glu Ser Arg 740745 750 Val Ser Ser Asp Leu Ser Arg Ile Leu Gln Leu Leu Gln Lys Pro 755760 765 Met Pro Gln Gly His Ala Ser Tyr Ile Leu Glu Ala Pro Ala Ser 770775 780 Asn Asp Leu Ala Leu Val Pro Ile Ala Ser Glu Thr Thr Ser Pro 785790 795 Gly Pro Arg Leu Pro Gln Gly Phe Leu Pro Pro Ala Gln Thr Pro 800805 810 Ser Tyr Gly Asp Leu Asp Asp Cys Ser Pro Lys His Arg Asn Ser 815820 825 Ser Pro Arg Met Pro His Leu Ala Val Ala Met Asp Lys Thr Leu 830835 840 Ala Pro Ser Ser Glu Gln Glu Gln Pro Glu Gly Leu Trp Pro Pro 845850 855 Leu Ala Ser Pro Leu His Pro Leu Glu Val Gln Gly Leu Ile Cys 860865 870 Gly Pro Cys Phe Ser Ser Leu Pro Glu His Leu Gly Ser Val Pro 875880 885 Lys Gln Leu Asp Phe Gln Arg His Gly Ser Asp Pro Gly Phe Ala 890895 900 Gly Ser Trp Gly His 905 27 686 PRT Homo sapiens misc_featureIncyte ID No 2522075CD1 27 Met Ala Glu Ala Ala Glu Pro Glu Gly Val AlaPro Gly Pro Gln 1 5 10 15 Gly Pro Pro Glu Val Pro Ala Pro Leu Ala GluArg Pro Gly Glu 20 25 30 Pro Gly Ala Ala Gly Gly Glu Ala Glu Gly Pro GluGly Ser Glu 35 40 45 Gly Ala Glu Glu Ala Pro Arg Gly Ala Ala Ala Val LysGlu Ala 50 55 60 Gly Gly Gly Gly Pro Asp Arg Gly Pro Glu Ala Glu Ala ArgGly 65 70 75 Thr Arg Gly Ala His Gly Glu Thr Glu Ala Glu Glu Gly Ala Pro80 85 90 Glu Gly Ala Glu Val Pro Gln Gly Gly Glu Glu Thr Ser Gly Ala 95100 105 Gln Gln Val Glu Gly Ala Ser Pro Gly Arg Gly Ala Gln Gly Glu 110115 120 Pro Arg Gly Glu Ala Gln Arg Glu Pro Glu Asp Ser Ala Ala Pro 125130 135 Glu Arg Gln Glu Glu Ala Glu Gln Arg Pro Glu Val Pro Glu Gly 140145 150 Ser Ala Ser Gly Glu Ala Gly Asp Ser Val Asp Ala Glu Gly Pro 155160 165 Leu Gly Asp Asn Ile Glu Ala Glu Gly Pro Ala Gly Asp Ser Val 170175 180 Glu Ala Glu Gly Arg Val Gly Asp Ser Val Asp Ala Glu Gly Pro 185190 195 Ala Gly Asp Ser Val Asp Ala Glu Gly Pro Leu Gly Asp Asn Ile 200205 210 Gln Ala Glu Gly Pro Ala Gly Asp Ser Val Asp Ala Glu Gly Arg 215220 225 Val Gly Asp Ser Val Asp Ala Glu Gly Pro Ala Gly Asp Ser Val 230235 240 Asp Ala Glu Gly Arg Val Gly Asp Ser Val Glu Ala Gly Asp Pro 245250 255 Ala Gly Asp Gly Val Glu Ala Gly Val Pro Ala Gly Asp Ser Val 260265 270 Glu Ala Glu Gly Pro Ala Gly Asp Ser Met Asp Ala Glu Gly Pro 275280 285 Ala Gly Arg Ala Arg Arg Val Ser Gly Glu Pro Gln Gln Ser Gly 290295 300 Asp Gly Ser Leu Ser Pro Gln Ala Glu Ala Ile Glu Val Ala Ala 305310 315 Gly Glu Ser Ala Gly Arg Ser Pro Gly Glu Leu Ala Trp Asp Ala 320325 330 Ala Glu Glu Ala Glu Val Pro Gly Val Lys Gly Ser Glu Glu Ala 335340 345 Ala Pro Gly Asp Ala Arg Ala Asp Ala Gly Glu Asp Arg Val Gly 350355 360 Asp Gly Pro Gln Gln Glu Pro Gly Glu Asp Glu Glu Arg Arg Glu 365370 375 Arg Ser Pro Glu Gly Pro Arg Glu Glu Glu Ala Ala Gly Gly Glu 380385 390 Glu Glu Ser Pro Asp Ser Ser Pro His Gly Glu Ala Ser Arg Gly 395400 405 Ala Ala Glu Pro Glu Ala Gln Leu Ser Asn His Leu Ala Glu Glu 410415 420 Gly Pro Ala Glu Gly Ser Gly Glu Ala Ala Arg Val Asn Gly Arg 425430 435 Arg Glu Asp Gly Glu Ala Ser Glu Pro Arg Ala Leu Gly Gln Glu 440445 450 His Asp Ile Thr Leu Phe Val Lys Ala Gly Tyr Asp Gly Glu Ser 455460 465 Ile Gly Asn Cys Pro Phe Ser Gln Arg Leu Phe Met Ile Leu Trp 470475 480 Leu Lys Gly Val Ile Phe Asn Val Thr Thr Val Asp Leu Lys Arg 485490 495 Lys Pro Ala Asp Leu Gln Asn Leu Ala Pro Gly Thr Asn Pro Pro 500505 510 Phe Met Thr Phe Asp Gly Glu Val Lys Thr Asp Val Asn Lys Ile 515520 525 Glu Glu Phe Leu Glu Glu Lys Leu Ala Pro Pro Arg Tyr Pro Lys 530535 540 Leu Gly Thr Gln His Pro Glu Ser Asn Ser Ala Gly Asn Asp Val 545550 555 Phe Ala Lys Phe Ser Ala Phe Ile Lys Asn Thr Lys Lys Asp Ala 560565 570 Asn Glu Ile His Glu Lys Asn Leu Leu Lys Ala Leu Arg Lys Leu 575580 585 Asp Asn Tyr Leu Asn Ser Pro Leu Pro Asp Glu Ile Asp Ala Tyr 590595 600 Ser Thr Glu Asp Val Thr Val Ser Gly Arg Lys Phe Leu Gly Gly 605610 615 Asp Glu Leu Thr Leu Ala Asp Cys Asn Leu Leu Pro Lys Leu His 620625 630 Ile Ile Lys Ile Val Ala Lys Lys Tyr Arg Asp Phe Glu Phe Pro 635640 645 Ser Glu Met Thr Gly Ile Trp Arg Tyr Leu Asn Asn Ala Tyr Ala 650655 660 Arg Asp Glu Phe Thr Asn Thr Cys Pro Ala Asp Gln Glu Ile Glu 665670 675 His Ala Tyr Ser Asp Val Ala Lys Arg Met Lys 680 685 28 2984 DNAHomo sapiens misc_feature Incyte ID No 7475353CB1 28 gttggcagaagggtcccggg cccagagcca gcggggccgt gctgagacgg cgtacgtgcc 60 ctgcgtgagtgcgtggcggc ggcgcgtgcg ctaggggagt gggcggtgag gcctggtcca 120 cgtgcgtcccttcccgggac ccccgcagct tggcgcccag cggctacgtg agccaaggca 180 cccggatgtccgcgcccctc tccgagtgac aagtcccggc ctccggtccc gcagtgcccg 240 cagcctcggccggcgtccac gcattgccat ggtgactgtg ggcaactact gcgaggccga 300 agggcccgtgggtccggcct ggatgcagga tggcctgagt ccctgcttct tcttcacgct 360 cgtgccctcgacgcggatgg ctctagggac tctggccttg gtgctggctc ttccctgcag 420 acgccgggagcggcccgctg gtgctgattc gctgtcttgg ggggccggcc ctcgcatctc 480 tccctacgtgctgcagctgc ttctggccac acttcaggcg gcgctgcccc tggccggcct 540 ggctggccgggtgggcactg cccggggggc cccactgcca agctatctac ttctggcctc 600 cgtgctggagagtctggccg gcgcctgtgg cctgtggctg cttgtcgtgg agcggagcca 660 ggcacggcagcgtctggcaa tgggcatctg gatcaagttc aggcacagcc ctggtctcct 720 gctcctctggactgtggcgt ttgcagctga gaacttggcc ctggtgtctt ggaacagccc 780 acagtggtggtgggcaaggg cagacttggg ccagcaggtt cagtttagcc tgtgggtgct 840 gcggtatgtggtctctggag ggctgtttgt cctgggtctc tgggcccctg gacttcgtcc 900 ccagtcctatacattgcagg ttcatgaaga ggaccaagat gtggaaagga gccaggttcg 960 gtcagcagcccaacagtcta cctggcgaga ttttggcagg aagctccgcc tcctgagtgg 1020 ctacctgtggcctcgaggga gtccagctct gcagctggtg gtgctcatct gcctggggct 1080 catgggtttggaacgggcac tcaatgtgtt ggtgcctata ttctatagga acattgtgaa 1140 cttgctgactgagaaggcac cttggaactc tctggcctgg actgttacca gttacgtctt 1200 cctcaagttcctccaggggg gtggcactgg cagtacaggc ttcgtgagca acctgcgcac 1260 cttcctgtggatccgggtgc agcagttcac gtctcggcgg gtggagctgc tcatcttctc 1320 ccacctgcacgagctctcac tgcgctggca cctggggcgc cgcacagggg aggtgctgcg 1380 gatcgcggatcggggcacat ccagtgtcac agggctgctc agctacctgg tgttcaatgt 1440 catccccacgctggccgaca tcatcattgg catcatctac ttcagcatgt tcttcaacgc 1500 ctggtttggcctcattgtgt tcctgtgcat gagtctttac ctcaccctga ccattgtggt 1560 cactgagtggagaaccaagt ttcgtcgtgc tatgaacaca caggagaacg ctacccgggc 1620 acgagcagtggactctctgc taaacttcga gacggtgaag tattacaacg ccgagagtta 1680 cgaagtggaacgctatcgag aggccatcat caaatatcag ggtttggagt ggaagtcgag 1740 cgcttcactggttttactaa atcagaccca gaacctggtg attgggctcg ggctcctcgc 1800 cggctccctgctttgcgcat actttgtcac tgagcagaag ctacaggttg gggactatgt 1860 gctctttggcacctacatta tccagctgta catgcccctc aactggtttg gcacctacta 1920 caggatgatccagaccaact tcattgacat ggagaacatg tttgacttgc tgaaagagga 1980 gacagaagtgaaggaccttc ctggagcagg gccccttcgc tttcagaagg gccgtattga 2040 gtttgagaacgtgcacttca gctatgccga tgggcgggag actctgcagg acgtgtcttt 2100 cactgtgatgcctggacaga cacttgccct ggtgggccca tctggggcag ggaagagcac 2160 aattttgcgcctgctgtttc gcttctacga catcagctct ggctgcatcc gaatagatgg 2220 gcaggacatttcacaggtga cccaggcctc tctccggtct cacattggag ttgtgcccca 2280 agacactgtcctctttaatg acaccatcgc cgacaatatc cgttacggcc gtgtcacagc 2340 tgggaatgatgaggtggagg ctgctgctca ggctgcaggc atccatgatg ccattatggc 2400 tttccctgaagggtacagga cacaggtggg cgagcgggga ctgaagctga gcggcgggga 2460 gaagcagcgcgtcgccattg cccgcaccat cctcaaggct ccgggcatca ttctgctgga 2520 tgaggcaacgtcagcgctgg atacatctaa tgagagggcc atccaggctt ctctggccaa 2580 agtctgtgccaaccgcacca ccatcgtagt ggcacacagg ctctcaactg tggtcaatgc 2640 tgaccagatcctcgtcatca aggatggctg catcgtggag aggggacgac acgaggctct 2700 gttgtcccgaggtggggtgt atgctgacat gtggcagctg cagcagggac aggaagaaac 2760 ctctgaagacactaagcctc agaccatgga acggtgacaa aagtttggcc acttccctct 2820 caaagactaacccagaaggg aataagatgt gtctcctttc cctggcttat ttcatcctgg 2880 tcttggggtatggtgctagc tatggtaagg gaaagggacc tttccgaaaa acatcttttg 2940 gggaaataaaaatgtggact gtgaaaaaaa aaaaaaaaaa aaaa 2984 29 1846 DNA Homo sapiensmisc_feature Incyte ID No 3107278CB1 29 aatactatca gtcttccctg cgtacggtcggaactattcc ccttcgccac tgccccctgg 60 gaggctgcgg gcaacggagc aacagcagcggcgcggacgg aggcgaacac cacccctcat 120 cccctccgga caagggggac aacgcctccaactgtgactg ccgcgcatgg gactacggca 180 tccgcgccgg cctcgtccag aacgtggtcagcaagtggga tctgtgtgtg ataatgcctg 240 gaaggtccat atcgctaagt tctccttactggtggattaa tctttggtac ctaataactg 300 gatgcattgc tgactgggtc ggccggcggcctgtgctgct gttttccatc atcttcattc 360 tgatctttgg actgactgtg gcactgtcagtgaatgtgac aatgttcagc acactcaggt 420 tctttgaagg attttgcctg gctggaatcattctcacctt gtatgcttta cgaatagagc 480 tgtgcccccc tggaaaacgg ttcatgattacgatggtggc gagcttcgtg gccatggcgg 540 gccagttcct catgcctggg ctagccgccctgtgccggga ttggcaggtg ctgcaggccc 600 tcatcatctg ccccttcctg ctcatgctgctctactggtc gatattcccc gagtccctcc 660 ggtggctaat ggccacccag cagtttgagtctgcaaagag gctgatcctc cacttcacac 720 agaagaatcg catgaaccct gagggcgacatcaagggtgt gataccagag ctggagaaag 780 agctttcccg gaggcccaag aaggtctgcatcgtgaaggt ggtggggaca cggaacctgt 840 ggaagaacat tgtggtcctg tgtgtgaactcgctgacggg gtacgggatc caccactgct 900 ttgccaggag catgatgggc cacgaggtgaaggtgccgct cctggagaac ttctatgctg 960 actactatac cacggccagc atcgcgctggtgtcctgcct ggccatgtgc gtggtggtcc 1020 gattcctcgg gcgcagggga gggctgctgctcttcatgat cctcaccgcc ctggcctcgc 1080 tcctgcagct cggcctcctc aacctgattggaaagtacag ccagcaccca gactcaggga 1140 tgagtgacag cgtcaaggac aaattttccatcgcgttttc catcgtgggc atgtttgcct 1200 cccatgcggt ggggagcctc agcgtgttcttctgtgcgga gatcaccccg acggtgataa 1260 ggtgtggcgg gctggggctg gtgctggccagcgcgggctt cggcatgctg acggcaccca 1320 tcatcgagct gcacaaccag aaaggctacttcctgcacca catcatcttt gcctgctgca 1380 cgctcatctg catcatctgc atcctcctgctgcccgagag cagggaccag aacctgcctg 1440 agaacatttc taacggggag cactacacgcgccagccgct gctgccgcac aagaaggggg 1500 agcagccact gctgctcacc aacgccgagctcaaggacta ctcgggcctc cacgatgccg 1560 cagccgcggg tgacacactg cccgagggtgccacggccaa cggcatgaag gccatgtagc 1620 ccggcctgcg gaacccgggg ctccagggtctggggcagct tgggcacagg tttacagacc 1680 agggaccgaa cacgcagcca ggggtgggaaagatgacatc agccaagctg agcctctcaa 1740 ctggtgtggg gaaatcctgt ctttccaaaagtccaaggag cgcgggtcgg aggagacaaa 1800 ctctttggaa ataacccttt caagactttcttttctgccg ttaaaa 1846 30 1458 DNA Homo sapiens misc_feature Incyte IDNo 7473394CB1 30 atgcagaata ttaccaaaga atttggaaca ttcaaggcaa atgacaacatcaatttacaa 60 gtaaaggcag gagagattca tgcgttgctt ggagaaaacg gtgctggcaaatctacattg 120 atgaacgtgc tttccggatt attagagccg acatcaggga aaattttgatgcgtgggaaa 180 gaagtacaga tcacaagccc gacaaaagcc aatcaattag ggattgggatggtccatcag 240 cactttatgc ttgttgatgc ctttactgta acagaaaaca tcgtgttgggaagcgaacct 300 agtcgtgcag ggatgcttga ccataaaaaa gcgcgaaaag agatccaaaaagtttctgaa 360 caatatggat tatcagtcaa cccggatgct tatgttcgtg atatttcagttgggatggaa 420 caacgggtag aaattttaaa aacactttac cgaggagcag atgtactgatttttgatgag 480 ccgacagctg tattgacccc tcaggaaatt gatgaattaa tcgtgatcatgaaggaatta 540 gtcaaagaag gcaagtcaat cattttgatt acgcataagt tagatgaaatcaaagcagta 600 gctgaccgtt gtacagttat ccgccgtgga aaaggaatcg gtacagtcaacgttaaagac 660 gttacctcac agcaattagc tgatatgatg gtcggaagag cggtttcattcaaaacgatg 720 aaaaaagaag cgaagcctca agaagtcgtt ttgtctattg aaaatctagtggtaaaagaa 780 aatcgtggat tagaagccgt gaaaaacctg aacttagagg ttcgtgctggcgaagtactt 840 ggtatcgctg gaatcgatgg aaacgggcag tcggagttga tccaagctttgactggtttg 900 cgaaaggcag aaagcggaca tatcaagcta aaaggggaag acatcaccaataaaaaacct 960 cgaaagatca ctgaacatgg tgtaggacat gtgccagaag accgtcataaatacgggttg 1020 gtcctagata tgacattgtc tgaaaacatt gccctgcaaa cgtatcatcaaaaaccttac 1080 agtaaaaacg gtatgctgaa ttattcagtg ataaatgaac atgccagagaattgatcgaa 1140 gaatatgatg ttcgaacaac gaatgaactt gttcctgcaa aagctttatcaggcggaaat 1200 cagcaaaaag caatcatcgc tcggatagtc gaccgagatc ctgatctgttgatcgttgca 1260 aatccaactc gtgggctgga tgtaggtgcg atcgaattta ttcataaacgtctgatcgaa 1320 caaagggaca aatacaaagc agtgttattg attagtttcg aattagaagaaattttaaat 1380 gtttcggatc gtattgctgt tatccatgaa ggagaaatcg tcgggatcgttgatccgaaa 1440 gaaacatctg aaaattaa 1458 31 1234 DNA Homo sapiensmisc_feature Incyte ID No 7473900CB1 31 atgaagtccg gtcctggcat ccaagccgccatcgacctca cagcgggggc cgcagggggg 60 acagcgtgtg tactgactgg gcagcccttcgacacaataa aagtgaagat gcagacgttc 120 cctgacctgt acaagggcct caccgactgcttcctgaaga catacgccca agtgggtctc 180 cggggcttct acaagggcac cggcccggcacttatggcct acgtcgccga aaactcggtc 240 ctcttcatgt gctacgggtt ctgccagcagtttgtcagga aagtggctgg aatggacaag 300 caggcaaagc tgagtgatct ccagactgcagccgcggggt ccttcgcctc tgcatttgct 360 gcactggctc tctgccccac tgagcttgtgaagtgccggc tacagaccat gtatgaaatg 420 gagatgtcag ggaagatagc aaaaagccataatacaattt ggtctgtcgt gaagggtatc 480 cttaaaaagg atggcccctt gggcttctaccatggactct cgagtactct acttcaagaa 540 gtaccgggtt atttcttttt ctttggtggctatgaactga gccgatcgtt ttttgcgtca 600 gggagatcaa aagatgaact aggccctgtccatttgatgt taagtggtgg agttgctgga 660 atttgcctgt ggcttgtcgt gttcccagtggattgtatta aatccagaat tcaagttctt 720 tccatgtatg ggaaacaggc aggatttattggtaccctct taagtgttgt gagaaatgaa 780 ggaatagtag ccttatattc tggactgaaagctactatga ttcgagcaat ccctgccaat 840 ggggcactgt ttgtggccta cgaatacagcaggaagatga tgatgaaaca gttggaagca 900 tactgaagtg tcttggtgaa cctggatccgagtccatgag tttgaggact acagttcatc 960 acagggttca gcagagtaca agaccactgtctaattttga cttcatggga attttggttt 1020 tatcttccct tcttctaccc taaatcttaactttatggaa gggcctctat tttacatcat 1080 ataatttctg cccataattg tattgaaataggaaagttgc tgctcttgca cttgctggaa 1140 tgtacagggt gggctggttg gccctatgtacctaatctga aaaactaaat atcgttctgt 1200 cagggccttt gcataaagcc atttgtgtgtacat 1234 32 1255 DNA Homo sapiens misc_feature Incyte ID No 7475045CB132 gtgacctttc cccccagatc ccaggtccag gcccgccctc ggctggcagg tgtgggcaca 60gaggcagctg ggattggtcg cagctggcgg aggcgcgtcc caggctccgg cagaccgctg 120gaacagttga gccagagcag gtggactgct gagatagacc agggacacca ggcagccaca 180ggcctgtcag accaggaccc ttaccctcta gacatggcct cggtcccctg caaaccccag 240ccccgtagcc ctgcgaggtt acagacagcc taaacgccac caccacaggg cctgtgccgt 300gcccctgacc cgggcacaga aggccactgg cccggaggcc atggagacgg tgcccccagc 360agtggacctg gtgctgggtg cttctgcctg ctgcctggcc tgtgtcttca ccaaccccct 420ggaggtggtg aagacgcggc tgcagctgca gggggagctg caggcccggg gcacctaccc 480acggccctac catggcttca tagcctctgt cgctgctgtg gcccgagcag acgggctgtg 540gggcctgcag aaggggctgg ctgccggcct tctgtaccaa ggcctcatga atggcgttcg 600tttctactgc tacagcctgg cgtgccaggc tggcctcacg cagcaaccag gtggcaccgt 660ggttgcggga gccgtggcgg gggcactggg agccttcgtg gggagccctg cttacctgat 720caaaacgcag ctgcaagctc agacagtggc cgcagtggcc gtgggacacc agcacaatca 780ccagactgtc ctgggtgcct tggagaccat ctggcggcag caagggctct tggggctgtg 840gcagggcgtt ggtggggctg tgccccgagt catggtgggc tcagctgccc agctggccac 900cttcgcctct gccaaggcct gggtacagaa gcaacagtgg ctccctgagg acagctggct 960ggtggccctg gctgggggca tgatcagcag catagccgtg gttgtcgtca tgactccctt 1020cgatgtggtc agcacgcggc tatacaatca gccggtggac acagctggca ggggccagct 1080ctatgggggc ctcaccgact gcatggtgaa gatctggcgg caggagggcc ccctggcact 1140ctacaagggc ctgggccccg cctacctgcg cctgggcccc cacaccatcc tcagcatgct 1200cttctgggac gagcttcgga aactggctgg gcgggcccag cacaagggca cctag 1255 33 957DNA Homo sapiens misc_feature Incyte ID No 7475611CB1 33 ngccgcgctggccaccttgc ccatcaaacg caccggttcg gtgcgataca agatcatcgt 60 cgtcatcgtcatcgctgtcc tgtgggtgat cagttggacg acgaccggaa ggattttcag 120 atgagtgccaaggtcctgct gtcgaccgag cacctgtacg ccacccaccc gggccgtcct 180 atggtactgaccgacgttaa tgtctccttt cgcgccgggg ttcgcgtagc gatcctggga 240 gctaatggatccggtaagac gaccctcatg cgctgcctgt ccggttccct caaacccgcc 300 aagggtcacgtcaagagggg cgacatcgtt gtcagctacg ggcgcgctca acttcgtgag 360 caccgtcgagccgtccagct tgtgctgcaa gaccctgacg accagctctt tagcgccgat 420 gtcagccaggatgtctcctt cggccccatg aatatgggcc tcaaagttga cgaggtgcgt 480 gaccgggtctccgagtccct agaactgctc ggggccagtc atctggctga gcgtgccacg 540 tatcaactgtcctatggtga gcgcaagagg gtcgcggttg ccggtgccgt ggccatgcgc 600 ccggatctgctgctccttga tgagcccacc gccggacttg acccggttgg agtcacccag 660 atgttggaggccctggatcg gctgcgcgat catggaacaa cggtggcgat ggctacccac 720 gacgtcgacctggctctggc gtgggcgcag gaggcccttg tcgttgtcga cggtcaggtg 780 caccaaggaccgatcggcga gttacttgcc gatgccgaca ccgtgggacg ggcacacctg 840 caccttccgtggcccctcga gctcgcccgg cgcctcggtg ttcgggacct tcccaggacg 900 atggacgacgtcgtggcgat gctgtccgac aatccctcgc cagctccctc gaattga 957 34 2407 DNA Homosapiens misc_feature Incyte ID No 7475617CB1 34 gcggccgcgg cctcggcctcctcctctggg gcggcggcgg aggacagcag cgccatggag 60 gagctcgcta ctgagaaggaggcggaggag agccaccggc aagacagcgt gagcctgctc 120 accttcatcc tgctgctcacgctcaccatc ctcaccatct ggctcttcaa gcaccgccgg 180 gtgcgctttc tgcacgagaccgggctggcc atgatctatg ggctcatcgt tggggtgatc 240 ctgaggtatg gtacccctgctaccagtggc cgtgacaaat cactcagctg cactcaggaa 300 gacagggcct tcagtaccttattagtgaat gtcagcggaa agttcttcga atacactctg 360 aaaggagaaa tcagtcctggcaagatcaac agcgtagagc agaatgatat gctacggaag 420 gtaacattcg atccagaagtatttttcaac attcttctgc ctccaattat ttttcatgct 480 ggatacagct taaagaagagacactttttc agaaatcttg gatctatact ggcctatgcc 540 ttcttgggga ctgctgtttcatgcttcatt attggaaatc tcatgtatgg tgtggtgaag 600 ctcatgaaga ttatgggacagctctcagat aaattttact acacagattg tctctttttt 660 ggagcaatca tctctgccactgacccagtg actgtgctgg cgatatttaa tgaattgcat 720 gcagacgtgg atctttacgcacttcttttt ggagagagcg tcctaaatga tgctgttgcc 780 attgtactgt cctcgtctattgttgcctac cagccagcgg gactgaacac tcacgccttt 840 gatgctgctg ccttttttaagtcagttggc atttttctag gtatatttag tggctctttt 900 accatgggag ctgtgactggtgttgtgact gctctagtga ctaagtttac caaactgcac 960 tgcttccccc tgctggagacggcgctgttc ttcctcatgt cctggagcac gtttctcttg 1020 gcagaagcct gcggatttacaggtgttgta gctgtccttt tctgtggaat cacacaagct 1080 cattacacct acaacaatctgtcggtggaa tcaagaagtc gaaccaagca gctctttgag 1140 gtgttacatt tcctggcagagaacttcatc ttctcctaca tgggcctggc actgtttacc 1200 ttccagaagc acgttttcagccccattttc atcatcggag cttttgttgc catcttcctg 1260 ggcagagccg cgcacatctacccgctctcc ttcttcctca acttgggcag aaggcataag 1320 attggctgga attttcaacacatgatgatg ttttcaggcc tcaggggagc aatggcattt 1380 gcgttggcca tccgtgacacggcatcctat gctcgccaga tgatgttcac gaccaccctt 1440 ctcattgtgt tcttcactgtctggatcatt ggaggaggca cgacacccat gttgtcatgg 1500 cttaacatca gagttggcgtcgaggagccc tccgaagagg accagaatga acaccactgg 1560 cagtacttca gagttggtgttgaccccgat caagacccac cacccaacaa cgacagcttt 1620 caagtcttac aaggggacggcccagattct gccagaggaa accggacaaa acaggagagc 1680 gcatggatat tcaggctgtggtacagcttt gatcacaatt atctgaagcc catcctcaca 1740 cacagtggtc ccccactaaccaccacgctc cccgcctggt gtggcttact agctcgatgt 1800 ctgaccagtc cccaggtgtacgataaccaa gagccactga gagaggaaga ctctgatttc 1860 atcctgaccg aaggcgacctgacattgacc tacggggaca gcacagtgac tgcaaatggc 1920 tcctcaagtt cgcacaccgcctccacgagt ctggagggca gccggagaac gaagagcagc 1980 tcggaggaag tgctggagcgagacctggga atgggagacc agaaggtttc gagccggggc 2040 acccgcctag tgtttcccctggaagataat gcttgacttt ccccccaagc cctggcgcga 2100 tggggtaggc tcccgatgggactgaagatt tgaaaataca tccacgaaca tttcaacatg 2160 gaacgaagaa ttatagttccttctctggct atatccataa agaacgtagt tatgaaatgt 2220 ttaaaaccaa aggcaaatagtgttatactc ttattttttg attaatctga ggaaaggagg 2280 tatttagaaa ctgatgatggtatcactgca aaaagcattc aacttttttt tttttggtgg 2340 agatggtgtt ccactctgtcacccaggctg gagtgcggtg ccttggtctg ggcccactgc 2400 aacctct 2407 35 2767DNA Homo sapiens misc_feature Incyte ID No 7473314CB1 35 atggagggctctgggggcgg tgcgggcgag cgggcgccgc tgctgggcgc gcggcgggcg 60 gcggcggccgcggcggctgg ggcgttcgcg ggccggcgcg cggcgtgcgg ggccgtgctg 120 ctgacggagctgctggagcg cgccgctttc tacggcatca cgtccaacct ggtgctattc 180 ctgaacggggcgccgttctg ctgggagggc gcgcaggcca gcgaggcgct gctgctcttc 240 atgggcctcacctacctggg ctcgccgttc ggaggctggc tggccgacgc gcggctgggc 300 cgggcgcgcgccatcctgct gagcctggcg ctctacctgc tgggcatgct ggccttcccg 360 ctgctggccgcgcccgccac gcgagccgcg ctctgcggtt ccgcgcgcct gctcaactgc 420 acggcgcctggtcccgacgc cgccgcccgc tgctgctcac cggccacctt cgcggggctg 480 gtgctggtgggcctgggcgt ggccaccgtc aaggccaaca tcacgccctt cggcgccgac 540 caggttaaagatcgaggtcc ggaagccact aggagatttt ttaattggtt ttattggagc 600 attaacctgggagcgatcct gtcgttaggt ggcattgcct atattcagca gaacgtcagc 660 tttgtcactggttatgcgat ccccactgtc tgcgtcggcc ttgcttttgt ggccttcctc 720 tgtggccagagcgttttcat caccaagcct cctgatggca gtgccttcac cgatatgttc 780 aagatactgacgtattcctg ctgttcccag aagcgaagtg gagagcgcca gagtaatggt 840 gaaggcattggagtctttca gcaatcttct aaacaaagtc tgtttgattc atgtaagatg 900 tctcatggtgggccatttac agaagagaaa gtggaagatg tgaaagctct ggtcaagatt 960 gtccctgttttcttggcttt gataccttac tggacagtgt atttccaaat gcagacaaca 1020 tatgttttacagagtcttca tttgaggatt ccagaaattt caaatattac aaccactcct 1080 cacacgctccctgcagcctg gctgaccatg tttgatgctg tgctcatcct cctgctcatc 1140 cctctgaaggacaaactggt cgatcccatt ttgagaagac atggcctgct cccatcctcc 1200 ctgaagaggatcgccgtggg catgttcttt gtcatgtgct cagcctttgc tgcaggaatt 1260 ttggagagtaaaaggctgaa ccttgttaaa gagaaaacca ttaatcagac catcggcaac 1320 gtcgtctaccatgctgccga tctgtcgctg tggtggcagg tgccgcagta cttgctgatt 1380 gggatcagcgagatctttgc aagtatcgca ggcctggaat ttgcatactc agctgccccc 1440 aagtccatgcagagtgccat aatgggcttg ttctttttct tctctggcgt cgggtcgttc 1500 gtgggttctggactgctggc actggtgtct atcaaagcca tcggatggat gagcagtcac 1560 acagactttggtaatattaa cggctgctat ttgaactatt actttttcct tctggctgct 1620 attcaaggagctaccctcct gcttttcctc attatttctg tgaaatatga ccatcatcga 1680 gaccatcagcgatcaagagc caatggcgtg cccaccagca ggagggcctg accttcctga 1740 ggccatgtgcggtttctgag gctgacatgt cagtaactga ctggggtgca ctgagaacag 1800 gcaagactttaaattcccat aaaatgtctg acttcactga aacttgcatg ttgcctggat 1860 tgatttcttctttccctcta tccaaaggag cttggtaagt gccttactgc agcgtgtctc 1920 ctggcacgctgggccctccg ggaggagagc tgcagatttc gagtatgtcg cttgtcattc 1980 aaggtctctgtgaatcctct agctgggttc ccttttttac agaaactcac aaatggagat 2040 tgcaaagtcttggggaactc cacgtgttag ttggcatccc agtttcttaa acaaatagta 2100 tcacctgcttcccatagcca tatctcactg taaaaaaaaa aattaataaa ctgttactta 2160 tatttaagaaagtgaggatt tttttttttt aaagataaaa gcatggtcag atgctgcaag 2220 gattttacataaatgccata tttatggttt ccttcctgag aacaatcatg ctcttgccat 2280 gttctttgatttaggctggt agtaaacaca tttcatctgc tgcttcaaaa agtacttact 2340 ttttaaaccatcaacattac ttttctttct taaggcaagg catgcataag agtcatttga 2400 gaccatgtgtcccatctcaa gccacagagc aactcacggg gtacttcaca ccttacctag 2460 tcagagtgcttatatatagc tttattttgg tacgattgag actaaagact gatcatggtt 2520 gtatgtaaggaaaacattct tttgaacaga aatagtgtaa ttaaaaataa ttgaaagtgt 2580 taaatgtgaacttgagctgt ttgaccagtc acatttttgt attgttactg tacgtgtatc 2640 tggggcttctccgtttgtta atactttttc tgtatttgtt gctgtatttt tggcataact 2700 ttattataaaaagcatctca aatgcgaaat ccaaaaaaaa aaaaaaaaaa gatcggccgc 2760 aagctta 276736 2182 DNA Homo sapiens misc_feature Incyte ID No 70356714CB1 36gcagtccgct cagccgaggc agctctgttc atggcgttct cgaagctctt ggagcaagcc 60ggaggcgtgg gcctcttcca gaccctgcag gtgctcacct tcatcctccc ctgcctcatg 120ataccttccc agatgctcct ggagaacttc tcagccgcca tcccaggcca ccgatgctgg 180acacacatgc tggacaatgg ctctgcggtt tccacaaaca tgacccccaa ggcccttctg 240accatctcca tcccgccagg ccccaaccag gggccccacc agtgccgccg cttccgccag 300ccacagtggc agctcttgga ccccaatgcc acggccacca gctggagcga agctgacacg 360gagccgtgtg tggacggctg ggtctatgac cgcagcgtct tcacctccac catcgtggcc 420aagtgggacc tggtgtgcag ctcccagggc ttgaagcccc taagccagtc catcttcatg 480tccgggatcc tggtgggctc ctttatctgg ggcctcctct cctaccggtt tgggaggaag 540ccgatgctga gctggtgctg cctgcagttg gccgtggcgg gcaccagcac catcttcgcc 600ccaacattcg tcatctactg cggcctgcgg ttcgtggccg cttttgggat ggccggcatc 660tttctgagtt cactgacact gatggtggag tggaccacga ccagcaggag ggcggtcacc 720atgacggtgg tgggatgtgc cttcagcgca ggccaggcgg cgctgggcgg cctggccttt 780gccctgcggg actggaggac tctccagctg gcagcatcag tgcccttctt tgccatctcc 840ctgatatcct ggtggctgcc agaatccgcc cggtggctga ttattaaggg caaaccagac 900caagcacttc aggagctcag aaaggtggcc aggataaatg gccacaagga ggccaagaac 960ctgaccatag aggtgctgat gtccagcgtg aaggaggagg tggcctctgc aaaggagccg 1020cggtcggtgc tggacctgtt ctgcgtgccc gtgctccgct ggaggagctg cgccatgctg 1080gtggtgaatt tctctctatt gatctcctac tatgggctgg tcttcgacct gcagagcctg 1140ggccgtgaca tcttcctcct ccaggccctc ttcggggccg tggacttcct gggccgggcc 1200accactgccc tcttgctcag tttccttggc cgccgcacca tccaggcggg ttcccaggcc 1260atggccggcc tcgccattct agccaacatg ctggtgccgc aagatttgca gaccctgcgt 1320gtggtctttg ctgtgctggg aaagggatgt tttgggataa gcctaacctg cctcaccatc 1380tacaaggctg aactctttcc aacgccagtg cggatgacag cagatggcat tctgcataca 1440gtgggccggc tgggggctat gatgggtccc ctgatcctga tgagccgcca agccctgccc 1500ctgctgcctc ctctcctcta tggcgttatc tccattgctt ccagcctggt tgtgctgttc 1560ttcctcccgg agacccaggg acttccgctc cctgacacta tccaggacct ggagagccag 1620aaatcaacag cagcccaggg caaccggcaa gaggccgtca ctgtggaaag tacctcgctc 1680tagaaattgt gcctgcatgg agccccttta gtcaaagact cctggaaagg agttgcctct 1740tctccaatca gagcgtggag gcgagttggg cgacttcaag ggcctggcat ggcagaggcc 1800aggcagccgt ggccgagtgg acagcgtggc cgtctgctgt ggctgaaggc agcttccaca 1860gctcactcct cttctccctg ccctgatcag attccccacc ttacccgggc cctacaggag 1920cctgtgcaga tggccatgcc caaccaataa cgagacggtt cccctccctt tccctgccag 1980gctcatgtct ttacaccttc actcagccac gccaaccaga gactgggttc caatctcacc 2040ccaccacata cagagccctc atctgtgaaa tgagaatgat cacgtgaccc accccccagg 2100gcaggtatca gggtgaactg atcttagcac cggccaaata aatggaacct gctgagagag 2160ctgccagaaa aaaaaaaaaa aa 2182 37 2811 DNA Homo sapiens misc_featureIncyte ID No 7611491CB1 37 cagacgggcc tggggcaggc atggcggatt ccagcgaaggcccccgcgcg gggcccgggg 60 aggtggctga gctccccggg gatgagagtg gcaccccaggtggggaggct tttcctctct 120 cctccctggc caatctgttt gagggggagg atggctccctttcgccctca ccggctgatg 180 ccagtcgccc tgctggccca ggcgatgggc gaccaaatctgcgcatgaag ttccaggcgc 240 cttccgcaag ggggtgccca accccatcga tctgctggagtccaccctat atgagtcctc 300 ggtggtgcct gggcccaaga aagcacccat ggactcactgtttgactacg gcacctatcg 360 tcaccactcc agtgacaaca agaggtggag gaagaagatcatagagaagc agccgcagag 420 ccccaaagcc cctgcccctc agccgccccc catcctcaaagtcttcaacc ggcctatcct 480 ctttgacatc gtgtcccggg gctccactgc tgacctggacgggctgctcc cattcttgct 540 gacccacaag aaacgcctaa ctgatgagga gtttcgagagccatctacgg ggaagacctg 600 cctgcccaag gccttgctga acctgagcaa tggccgcaacgacaccatcc ctgtgctgct 660 ggacatcgcg gagcgcaccg gcaacatgag ggagttcattaactcgccct tccgtgacat 720 ctactatcga ggtcagacag ccctgcacat cgccattgagcgtcgctgca aacactacgt 780 ggaacttctc gtggcccagg gagctgatgt ccacgcccaggcccgtgggc gcttcttcca 840 gcccaaggat gaggggggct acttctactt tggggagctgcccctgtcgc tggctgcctg 900 caccaaccag ccccacattg tcaactacct gacggagaacccccacaaga aggggacatg 960 cggcgccagg actcgcgagg caacacagtg ctgcatgcgctggtggccat tgctgacaac 1020 acccgtgaga acaccaagtt tgttaccaag atgtacgacctgctgctgct caagtgtgcc 1080 cgcctcttcc ccgacagcaa cctggaggcc gtgctcaacaacgacggcct ctcgcccctc 1140 atgatgatgg ctgccaagac gggcaagatt gggatctttcagcacatcat ccggcgggag 1200 gtgacggatg aggacacacg gcacctgtcc cgcaagttcaaggactgggc ctatgggcca 1260 gtgtattcct cgctttatga cctctcctcc ctggacacgtgtggggaaga ggcctccgtg 1320 ctggagatcc tggtgtacaa cagcaagatt gagaaccgccacgagatgct ggctgtggag 1380 cccatcaatg aactgctgcg ggacaagtgg cgcaagttcggggccgtctc cttctacatc 1440 aacgtggtct cctacctgtg tgccatggtc atcttcactctcaccgccta ctaccagccg 1500 ctggagggca caccgccgta cccttaccgc accacggtggactacctgcg gctggctggc 1560 gaggtcatta cgctcttcac tggggtcctg ttcttcttcaccaacatcaa agacttgttc 1620 atgaagaaat gccctggagt gaattctctc ttcattgatggctccttcca gctgctctac 1680 ttcatctact ctgtcctggt gatcgtctca gcagccctctacctggcagg gatcgaggcc 1740 tacctggccg tgatggtctt tgccctggtc ctgggctggatgaatgccct ttacttcacc 1800 cgtgggctga agctgacggg gacctatagc atcatgatccagaagattct cttcaaggac 1860 cttttccgat tcctgctcgt ctacttgctc ttcatgatcggctacgcttc agccctggtc 1920 tccctcctga acccgtgtgc caacatgaag gtgtgcaatgaggaccagac caactgcaca 1980 gtgcccactt acccctcgtg ccgtgacagc gagaccttcagcaccttcct cctggacctg 2040 tttaagctga ccatcggcat gggcgacctg gagatgctgagcagcaccaa gtaccccgtg 2100 gtcttcatca tcctgctggt gacctacatc atcctcacctttgtgctgct cctcaacatg 2160 ctcattgccc tcatgggcga gacagtgggc caggtctccaaggagagcaa gcacatctgg 2220 aagctgcagt gggccaccac catcctggac attgagcgctccttccccgt attcctgagg 2280 aaggccttcc gctctgggga gatggtcacc gtgggcaagagctcggacgg cactcctgac 2340 cgcaggtggt gcttcagggt ggatgaggtg aactggtctcactggaacca gaacttgggc 2400 atcatcaacg aggacccggg caagaatgag acctaccagtattatggctt ctcgcatacc 2460 gtgggccgcc tccgcaggga tcgctggtcc tcggtggtaccccgcgtggt ggaactgaac 2520 aagaactcga acccggacga ggtggtggtg cctctggacagcacggggaa cccccgctgc 2580 gatggccacc agcagggtta cccccgcaag tggaggactgatgacgcccc gctctaggga 2640 ctgcagccca gccccagctt ctctgcccac tcatttctagtccagccgca tttcagcagt 2700 gccttctggg gtgtcccccc acaccctgct tttggcccagaggcgaggga ccagtggagg 2760 ttcaaggagg cccaagaacc tgtggtcccc tggctctgcttcccaacctg g 2811 38 2074 DNA Homo sapiens misc_feature Incyte ID No171968CB1 38 tggaccccga ttctcacctg gactccaaaa gctatcttga cctactggcatctctgaccc 60 aaatcttaat tgcccccatc gccctctaca tccccccagc actgaccctcaccaggactc 120 cagccccaat tccatcccaa atctgtgtag catctgcttc tgccgattctaagagcccta 180 gcacctgcca agtcccccca ttacccacct tcccacactc agaagcctctttggtgggat 240 gctaatggga aggagtcttg cctctctgga ggcaggaggg gctggccttgtgcccctccg 300 ggcctctgag aggtgggcgc aggagaacag cactcacgag gggacctccttcaccctggg 360 aaagggtggt ttctttgcta tttcacagtc acaggctgaa tccttcacttggccctgccc 420 accgtacagg tatgctcact gccggcttta gggaggccag aaaccaacctgctcctgcaa 480 aaagaatcca ggcttgttct gagtgcctgc tgtaggccag gcaagttggtcactgttgca 540 tgaggggcag tgcctctcac tcttgggcct gatgccaagg gaggtggcctgtcccggtcg 600 catgcagaca tcctggccat cccagccaca catgcacgtg agaggctgggtgccggcagg 660 gttcctgagg gactggaaga tgtggccccc tgcctgcctc cttcctcttgtgaatataag 720 gggccagttc ccagcccaaa gccccacccg gggccctcat gtttcatcaccaacaggcct 780 actgtctggc tccttttgac ctcatcaaag tccggctaca aaaccagacagagccaaggg 840 cccagccagg gagcccccca ccccggtacc aggggcccgt gcactgtgcagcctccatct 900 tccgggagga ggggccccgg gggctgttcc gaggagcctg ggccctgacgctgagggaca 960 cccccacggt ggggatctac ttcatcacct atgaagggct ctgtcgccagtacacaccag 1020 aaggccagaa tcccagctca gccacggtgc tggtggcagg gggctttgcaggcattgctt 1080 cctgggtggc agccacgccc ttagacgtga tcaagtcccg gatgcagatggatggactga 1140 gacgcagagt gtaccagggg atgctggact gcatggtgag cagcatccggcaggaaggac 1200 tgggagtctt cttccggggg gtcaccatca acagtgcccg cgcctttcccgtcaatgctg 1260 tcaccttcct cagctacgaa tatctcctcc gctggtgggg atgagccctgcggcaatgcc 1320 agcagctccc catcaggccc acggcctgga ggccagtttg agattggaggccaggttgaa 1380 agcttgcaaa tcagtgcaag aggctcagcc cttcctaacc aaggtgcctcccacccgcgc 1440 agatctgggc tgggcagaca cctgtgggag ccggaagcca gggggcctgtgcagcctccc 1500 tgtgtagctg gccttgactc ctttgcctcc cacatctgtg aaacagggagcatgaggcac 1560 aagtgagctg gcaagtggtg ctggtgacat cccagctcct gtcctgtgccttcacctctt 1620 tttttttttt tttttttttt ggggagaggg ggaggtcttt ctctcttggtcccccagggg 1680 cgtgggattc gcaggggcgg gtgagactcc tcgggttcat tggaaaccttcggcgttttc 1740 cacctttccg gggtctcaag cgcaattctt cctggcctta agccttcccaaggtacgctg 1800 ggagacatat tagcgcggcc cggcaacaca aacccaggta taaatttttgggtattttta 1860 aggctaagaa gacaggggtt taccccattg tcagcgccag ggttgggtcctggagatctc 1920 tctggatctt tggggagatc cggcccgggt ggtgggcctt ctcaagagttgcgcggggag 1980 attacacagg gctgtgagag gccccacccg ggcgccccgg ggtggccttacactcttctt 2040 aagggagcct cggaggactc cctttttgga aagg 2074 39 1340 DNAHomo sapiens misc_feature Incyte ID No 257274CB1 39 aggaacagcgccatgtgctc cgggctcctg gagctcctgc tgcccatctg gctctcctgg 60 accctggggacccgaggctc tgagccccgc agtgtgaacg atcccgggaa catgtccttt 120 gtgaaggagacggtggacaa gctgttgaaa ggctacgaca ttcgcctaag acccgacttc 180 gggggtcccccggtctgcgt ggggatgaac atcgacatcg ccagcatcga catggtttcc 240 gaagtcaacatgagattctg gctgcaggaa aggggaacga agacagtggt ctgtgcgttc 300 caggggtgtctctgcggttt ttccaaggct gcctcctgga ctgggagacc cgggcccggc 360 accgccagtctctgtccgag gtgctgacag gcttccgctg cttcagagag cgggaggccg 420 cgcctaggcgggctctcaga ggagccgctc taccgggaga gtcggaggct ggtgacccag 480 tgtcacttaggtcttctgtg aatgcagact ggattcaata ttctgacctg tgggaagcgg 540 aggtcagtaccccgaggtgc gaagcgggct tttgccagga gtgctttagg acgccaggga 600 atcaggagaaggatggccct ttcatttgtt aattgagctg aaacgccgtg ggatttgaaa 660 actagtttagttttctgcgg agggacactc tggaaggagc atttgtaaac aatatttgtt 720 ttttggaagaaattgtttgg caacttttct ttcggacata caacattgag aatacagtga 780 gacatggttttagatccact ctgtaggctt cttaactctc gtgtacgtcg gaatcacgtg 840 ggcaaacttgctttaaatgc gtgcctgcta gttcctcact ccaagggatt ctgatcaaga 900 taggctggagtcttggggtc cctgcattta aaactacttc ttcaaatatt ttgaagcggg 960 tattttgtggacaatatttt gagaaacttt gcagtaagtc acagatatat gaatatatac 1020 aaataaagtaaaactatttt taaaaataga cgttagtgag atacttttaa aatacctacc 1080 actaaggatcttataggaag aaacttttga ccacgccaag ctgttctcat taatttttca 1140 ctgttaatctaaagctttta aatttacaat cccatgtatt taaaaatgta cttttttcca 1200 aagtatatcacttaggacat ttgtaagtca aatattgtat cagtaaaagt gttagcaagg 1260 aacacagaaggaatgtgact gcataaatta ccttacagta aaaattaaca tgtctatttt 1320 actttttatgtaatacatta 1340 40 6027 DNA Homo sapiens misc_feature Incyte ID No6355991CB1 40 atggagcaaa cagtgcttgt accaccagga cctgacagct tcaacttcttcaccagagaa 60 tctcttgcgg ctattgaaag acgcattgca gaagaaaagg caaagaatcccaaaccagac 120 aaaaaagatg acgacgaaaa tggcccaaag ccaaatagtg acttggaagctggaaagaac 180 cttccattta tttatggaga cattcctcca gagatggtgt cagagcccctggaggacctg 240 gacccctact atatcaataa gcagactttt atagtattga ataaagggaaggccatcttc 300 cggttcagtg ccacctctgc cctgtacatt ttaactccct tcaatcctcttaggaaaata 360 gctattaaga ttttggtaca ttcattattc agcatgctaa ttatgtgcactattttgaca 420 aactgtgtgt ttatgacaat gagtaaccct cctgattgga caaagaatgtagagtacacc 480 ttcacaggaa tatatacttt tgaatcactt ataaaaatta ttgcaaggggattctgttta 540 gaagatttta ctttccttcg ggatccatgg aactggctcg atttcactgtcattacattt 600 gcgtacgtca cagagtttgt ggacctgggc aatgtctcgg cattgagaacattcagagtt 660 ctccgagcat tgaagacgat ttcagtcatt ccaggcctga aaaccattgtgggagccctg 720 atccagtctg tgaagaagct ctcagatgta atgatcctga ctgtgttctgtctgagcgta 780 tttgctctaa ttgggctgca gctgttcatg ggcaacctga ggaataaatgtatacaatgg 840 cctcccacca atgcttcctt ggaggaacat agtatagaaa agaatataactgtgaattat 900 aatggtacac ttataaatga aactgtcttt gagtttgact ggaagtcatatattcaagat 960 tcaggatatc attatttcct ggagggtttt ttagatgcac tactatgtggaaatagctct 1020 gatgcagggc aatgtccaga gggatatatg tgtgtgaaag ctggtagaaatcccaattat 1080 ggctacacaa gctttgatac cttcagttgg gcttttttgt ccttgtttcgactaatgact 1140 caggacttct gggaaaatct ttatcaactg acattacgtg ctgctgggaaaacgtacatg 1200 atattttttg tattggtcat tttcttgggc tcattctacc taataaatttgatcctggct 1260 gtggtggcca tggcctacga ggaacagaat caggccacct tggaagaagcagaacagaaa 1320 gaggccgaat ttcagcagat gattgaacag cttaaaaagc aacaggaggcagctcagcag 1380 gcagcaacgg caactgcctc agaacattcc agagagccca gtgcagcaggcaggctctca 1440 gacagctcat ctgaagcctc taagttgagt tccaagagtg ctaaggaaagaagaaatcgg 1500 aggaagaaaa gaaaacagaa agagcagtct ggtggggaag agaaagatgaggatgaattc 1560 caaaaatctg aatctgagga cagcatcagg aggaaaggtt ttcgcttctccattgaaggg 1620 aaccgattga catatgaaaa gaggtactcc tccccacacc agtctttgttgagcatccgt 1680 ggctccctat tttcaccaag gcgaaatagc agaacaagcc ttttcagctttagagggcga 1740 gcaaaggatg tgggatctga gaacgacttc gcagatgatg agcacagcacctttgaggat 1800 aacgagagcc gtagagattc cttgtttgtg ccccgacgac acggagagagacgcaacagc 1860 aacctgagtc agaccagtag gtcatcccgg atgctggcag tgtttccagcgaatgggaag 1920 atgcacagca ctgtggattg caatggtgtg gtttccttgg ttggtggaccttcagttcct 1980 acatcgcctg ttggacagct tctgccagag gtgataatag ataagccagctactgatgac 2040 aatggaacaa ccactgaaac tgaaatgaga aagagaaggt caagttctttccacgtttcc 2100 atggactttc tagaagatcc ttcccaaagg caacgagcaa tgagtatagccagcattcta 2160 acaaatacag tagaagaact tgaagaatcc aggcagaaat gcccaccctgttggtataaa 2220 ttttccaaca tattcttaat ctgggactgt tctccatatt ggttaaaagtgaaacatgtt 2280 gtcaacctgg ttgtgatgga cccatttgtt gacctggcca tcaccatctgtattgtctta 2340 aatactcttt tcatggccat ggagcactat ccaatgacgg accatttcaataatgtgctt 2400 acagtaggaa acttggtatt cactgggatc tttacagcag aaatgtttctgaaaattatt 2460 gccatggatc cttactatta tttccaagaa ggctggaata tctttgacggttttattgtg 2520 acgcttagcc tggtagaact tggactcgcc aatgtggaag gattatctgttctccgttca 2580 tttcgattgc tgcgagtttt caagttggca aaatcttggc caacgttaaatatgctaata 2640 aagatcatcg gcaattccgg gggggctctg ggaaatttaa ccctcgtcttggccatcatc 2700 gtcttcattt ttgccgtggt cggcatgcag ctctttggta aaagctacaaagattgtgtc 2760 tgcaagatcg ccagtgattg tcaactccca cgctggcaca tgaatgacttcttccactcc 2820 ttcctgattg tgttccgcgt gctgtgtggg gagtggatag agaccatgtgggactgtatg 2880 gaggttgctg gtcaagccat gtgccttact gtcttcatga tggtcatggtgattggaaac 2940 ctagtggtac tgaatctctt tctggccttg cttctgagct catttagtgcagacaacctt 3000 gcagccactg atgatgataa tgaaatgaat aatctccaaa ttgctgtggataggatgcac 3060 aaaggagtag cttatgtgaa aagaaaaata tatgaattta ttcaacagtccttcattagg 3120 aaacaaaaga ttttagatga aattaaacca cttgatgatc taaacaacaagaaagacagt 3180 tgtatgtcca atcatacagc agaaattggg aaagatcttg actatcttaaagatgtaaat 3240 ggaactacaa gtggtatagg aactggcagc agtgttgaaa aatacattattgatgaaagt 3300 gattacatgt cattcataaa caaccccagt cttactgtga ctgtaccaattgctgtagga 3360 gaatctgact ttgaaaattt aaacacggaa gactttagta gtgaatcggatctggaagaa 3420 agcaaagaga aactgaatga aagcagtagc tcatcagaag gtagcactgtggacatcggc 3480 gcacctgtag aagaacagcc cgtagtggaa cctgaagaaa ctcttgaaccagaagcttgt 3540 ttcactgaag gttgtgtaca aagattcaag tgttgtcaaa tcaatgtggaagaaggcaga 3600 ggaaaacaat ggtggaacct gagaaggacg tgtttccgaa tagttgaacataactggttt 3660 gagaccttca ttgttttcat gattctcctt agtagtggtg ctctggcatttgaagatata 3720 tatattgatc agcgaaagac gattaagacg atgttggaat atgctgacaaggttttcact 3780 tacattttca ttctggaaat gcttctaaaa tgggtggcat atggctatcaaacatatttc 3840 accaatgcct ggtgttggct ggacttctta attgttgatg tttcattggtcagtttaaca 3900 gcaaatgcct tgggttactc agaacttgga gccatcaaat ctctcaggacactaagagct 3960 ctgagacctc taagagcctt atctcgattt gaagggatga gggtagttgtgaatgccctt 4020 ttaggagcaa ttccatccat catgaatgtg cttctggttt gtcttatattctggctaatt 4080 ttcagcatca tgggcgtaaa tttgtttgct ggcaaattct accactgtattaacaccaca 4140 actggtgaca ggtttgacat cgaagacgtg aataatcata ctgattgcctaaaactaata 4200 gaaagaaatg agactgctcg atggaaaaat gtgaaagtaa actttgataatgtaggattt 4260 gggtatctct ctttgcttca agttgccaca ttcaaaggat ggatggatataatgtatgca 4320 gcagttgatt ccagaaatgt agaactccag cctaagtatg aagaaagtctgtacatgtat 4380 ctttactttg ttattttcat catctttggg tccttcttca ccttgaacctgtttattggt 4440 gtcatcatag ataatttcaa ccagcagaaa aagaagtttg gaggtcaagacatctttatg 4500 acagaagaac agaagaaata ctataatgca atgaaaaaat taggatcgaaaaaaccgcaa 4560 aagcctatac ctcgaccagg aaacaaattt caaggaatgg tctttgacttcgtaaccaga 4620 caagtttttg acataagcat catgattctc atctgtctta acatggtcacaatgatggtg 4680 gaaacagatg accagagtga atatgtgact accattttgt cacgcatcaatctggtgttc 4740 attgtgctat ttactggaga gtgtgtactg aaactcatct ctctacgccattattatttt 4800 accattggat ggaatatttt tgattttgtg gttgtcattc tctccattgtaggtatgttt 4860 cttgccgagc tgatagaaaa gtatttcgtg tcccctaccc tgttccgagtgatccgtctt 4920 gctaggattg gccgaatcct acgtctgatc aaaggagcaa aggggatccgcacgctgctc 4980 tttgctttga tgatgtccct tcctgcgttg tttaacatcg gcctcctactcttcctagtc 5040 atgttcatct acgccatctt tgggatgtcc aactttgcct atgttaagagggaagttggg 5100 atcgatgaca tgttcaactt tgagaccttt ggcaacagca tgatctgcctattccaaatt 5160 acaacctctg ctggctggga tggattgcta gcacccattc tcaacagtaagccacccgac 5220 tgtgacccta ataaagttaa ccctggaagc tcagttaagg gagactgtgggaacccatct 5280 gttggaattt tcttttttgt cagttacatc atcatatcct tcctggttgtggtgaacatg 5340 tacatcgcgg tcatcctgga gaacttcagt gttgctactg aagaaagtgcagagcctctg 5400 agtgaggatg actttgagat gttctatgag gtttgggaga agtttgatcccgatgcaact 5460 cagttcatgg aatttgaaaa attatctcag tttgcagctg cgcttgaaccgcctctcaat 5520 ctgccacaac caaacaaact ccagctcatt gccatggatt tgcccatggtgagtggtgac 5580 cggatccact gtcttgatat cttatttgct tttacaaagc gggttctaggagagagtgga 5640 gagatggatg ctctacgaat acagatggaa gagcgattca tggcttccaatccttccaag 5700 gtctcctatc agccaatcac tactacttta aaacgaaaac aagaggaagtatctgctgtc 5760 attattcagc gtgcttacag acgccacctt ttaaagcgaa ctgtaaaacaagcttccttt 5820 acgtacaata aaaacaaaat caaaggtggg gctaatcttc ttataaaagaagacatgata 5880 attgacagaa taaatgaaaa ctctattaca gaaaaaactg atctgaccatgtccactgca 5940 gcttgtccac cttcctatga ccgggtgaca aagccaattg tggaaaaacatgagcaagaa 6000 ggcaaagatg aaaaagccaa agggaaa 6027 41 2168 DNA Homosapiens misc_feature Incyte ID No 70035348CB1 41 attagctttg cccgaagtttttccccacac tcttctttag catgctatta tggggaaagt 60 gaccactcct gggagcgggggtggtcgggg cggtttggtg gcggggaagc ggctgtaact 120 tctacgtgac catggtacctgttgaaaaca ccgagggccc cagtctgctg aaccagaagg 180 ggacagccgt ggagacggagggcagcggca gccggcatcc tccctgggcg agaggctgcg 240 gcatgtttac cttcctgtcatctgtcactg ctgctgtcag tggcctcctg gtgggttatg 300 aacttgggat catctctggggctcttcttc agatcaaaac cttattagcc ctgagctgcc 360 atgagcagga aatggttgtgagctccctcg tcattggagc cctccttgcc tcactcaccg 420 gaggggtcct gatagacagatatggaagaa ggacagcaat catcttgtca tcctgcctgc 480 ttggactcgg aagcttagtcttgatcctca gtttatccta cacggttctt atagtgggac 540 gcattgccat aggggtctccatctccctct cttccattgc cacttgtgtt tacatcgcag 600 agattgctcc tcaacacagaagaggccttc ttgtgtcact gaatgagctg atgattgtca 660 tcggcattct ttctgcctatatttcaaatt acgcatttgc caatgttttc catggctgga 720 agtacatgtt tggtcttgtgattcccttgg gagttttgca agcaattgca atgtattttc 780 ttcctccaag ccctcggtttctggtgatga aaggacaaga gggagctgct agcaaggttc 840 ttggaaggtt aagagcactctcagatacaa ctgaggaact cactgtgatc aaatcctccc 900 tgaaagatga atatcagtacagtttttggg atctgtttcg ttcaaaagac aacatgcgga 960 cccgaataat gataggactaacactagtat tttttgtaca aatcactggc caaccaaaca 1020 tattgttcta tgcatcaactgttttgaagt cagttggatt tcaaagcaat gaggcagcta 1080 gcctcgcctc cactggggttggagtcgtca aggtcattag caccatccct gccactcttc 1140 ttgtagacca tgtcggcagcaaaacattcc tctgcattgg ctcctctgtg atggcagctt 1200 cgttggtgac catgggcatcgtaaatctca acatccacat gaacttcacc catatctgca 1260 gaagccacaa ttctatcaaccagtccttgg atgagtctgt gatttatgga ccaggaaacc 1320 tgtcaaccaa caacaatactctcagagacc acttcaaagg gatttcttcc catagcagaa 1380 gctcactcat gcccctgagaaatgatgtgg ataagagagg ggagacgacc tcagcatcct 1440 tgctaaatgc tggattaagccacactgaat accagatagt cacagaccct ggggacgtcc 1500 cagctttttt gaaatggctgtccttagcca gcttgcttgt ttatgttgct gctttttcaa 1560 ttggtctagg accaagagatgttatcttta tcggacagtc aacaaacttg ccctctgctc 1620 cagagggtga cactatctctatctccaaga ctatttatta tgcagcctac aacaaggcta 1680 ttatacaaac agccttggaaagacagccta gagcaaagac agtcagtgcc ttttcccata 1740 agacatgaag aaatgtgagagacctacgga gaactggctc ccaacccaaa tatcctaaaa 1800 ctcaaatgtc tttctttctattcgaaacaa caaactagaa ttttgaaaaa ctcaaagacc 1860 atagagccta gctttttgctctgtttggtt ttatggagct gaaccagcct attggagggt 1920 gggtatcaat gttggaagcatgagtcatct gccgtaaaat ttaaacttag atttaaacaa 1980 ataactctgg ctcttaaaaattttgttcat tggatatttg cacagctaaa gattatgaca 2040 gctccaagga tgtggagcagcaggttctaa tttggaagtt tacctagtgg cttcatttca 2100 agacctactg ggtttaaggcaaagaggctg acattgcaga agcacaggtg tttcaaatca 2160 gattctgg 2168 42 2229DNA Homo sapiens misc_feature Incyte ID No 7472539CB1 42 atggaataccaggcgtccga ggtgatcggg cagcgtcagt cttcagccac taagccagga 60 agatctgggaaggagtcagt cacagagccc tgggccagag ttccaggggc tctgggagtg 120 gctgccaggcagatgcaccc caagtcaata atcacattca gagagataaa tggggagtac 180 actggggctgtggattttcc caggctagga gtccgtgctt ctgaggaaac agcgctcaga 240 gagctgaagatgagcaagga gctggcagca atggggcctg gagcttcagg ggacggggtc 300 aggactgagacagctccaca catagcactg gactccagag ttggtctgca cgcctacgac 360 atcagcgtggtggtcatcta ctttgtcttc gtcattgctg tggggatctg gtcgtccatc 420 cgtgcaagtcgagggaccat tggcggctat ttcctggccg ggagttggag catctctgat 480 gtccagcaatgtgggcagtg gcttgttcat cggcctggct gggacagggg ctgccggagg 540 ccttgccgtaggtggcttcg agtggaactg ctcctggccc ttggctgggt cttcgtccct 600 gtgtacatcgcagcaggtgt ggtcacaatg ccgcagtatc tgaagaagcg atttgggggc 660 cagaggatccaggtgtacat gtctgtcctg tctctcatcc tctacatctt caccaagatc 720 tcgactgacatcttctctgg agccctcttc atccagatgg cattgggctg gaacctgtac 780 ctctccacagggatcctgct ggtggtgact gccgtctaca ccattgcagg tggcctcatg 840 gccgtgatctacacagatgc tctgcagacg gtgatcatgg tagggggagc cctggtcctc 900 atgtttctgggctttcagga cgtgggctgg tacccaggcc tggagcagcg gtacaggcag 960 gccatccctaatgtcacagt ccccaacacc acctgtcacc tcccacggcc cgatgctttc 1020 cacattcttcgggaccctgt gagcggggac atcccttggc caggtctcat tttcgggctc 1080 acagtgctggccacctggtg ttggtgcaca gaccaggtca ttgtgcagcg gtctctctcg 1140 gccaagagtctgtctcatgc caagggaggc tccgtgctgg ggggctacct gaagatcctc 1200 cccatgttcttcatcgtcat gcctggcatg atcagccggg ccctgttccc agacgaggtg 1260 ggctgcgtggaccctgatgt ctgccaaaga atctgtgggg cccgagtggg atgttccaac 1320 attgcctaccctaagttggt catggccctc atgcctgttg gtctgcgggg gctgatgatt 1380 gccgtgatcatggccgctct catgagctca ctcacctcca tcttcaacag cagcagcacc 1440 ctgttcaccattgatgtgtg gcagcgcttc cgcaggaagt caacagagca ggagctgatg 1500 gtggtgggcagagtgtttgt ggtgttcctg gttgtcatca gcatcctctg gatccccatc 1560 atccaaagctccaacagtgg gcagctcttc gactacatcc aggctgtcac cagttacctg 1620 gccccacccatcaccgctct cttcctgctg gccatcttct gcaagagggt cacagagccc 1680 ggagctttctggggcctcgt gtttggcctg ggagtggggc ttctgcgtat gatcctggag 1740 ttctcatacccagcgccagc ctgtggggag gtggaccgga ggccagcagt gctgaaggac 1800 ttccactacctgtactttgc aatcctcctc tgcgggctca ctgccatcgt cattgtcatt 1860 ctcacacgcctcacatggtg gactcggaac tgccccctct ctgagctgga gaaggaggcc 1920 cacgagagcacaccggagat atccgagagg ccagccgggg agtgccctgc aggaggtgga 1980 gcggcagagaactcgagcct gggccaggag cagcctgaag ccccaagcag gtcctgggga 2040 aagttgctctggagctggtt ctgtgggctc tctggaacac cggagcaggc cctgagccca 2100 gcagagaaggctgcgctaga acagaagctg acaagcattg aggaggagcc actctggaga 2160 catgtctgcaacatcaatgc tgtccttttg ctggccatca acatcttcct ctggggctat 2220 tttgcgtga2229 43 1520 DNA Homo sapiens misc_feature Incyte ID No 817477CB1 43gcgcctcgtc gggcccttcc tctctacctg cctctccaac ccctctcggc cccgagccac 60ccggcagcgg gggtgggtgt gcagaggtgc ggcgtccaga accccggctc ctgcagaggc 120tctgggtggc agcagccctg ttaccgctta gatggcgcgc aggacagagc cccccgacgg 180gggctgggga tgggtggtgg tgctctcagc gttcttccag tcggcgcttg tgtttggggt 240gctccgctcc tttggggtct tcttcgtgga gtttgtggcg gcgtttgagg agcaggcagc 300gcgcgtctcc tggatcgcct ccataggaat cgcggtgcag cagtttggga gcccggtagg 360cagtgccctg agcacgaagt tcgggcccag gcccgtggtg atgactggag gcatcttggc 420tgcgctgggg atgctgctcg cctcttttgc tacttccttg acccacctat acctgagtat 480tgggttgctg tcaggctctg gctgggcttt gaccttcgct ccgaccctgg cctgcctgtc 540ctgttatttc tctcgccgac gatccctggc caccgggctg gcactgacag gcgtgggcct 600ctcctccttc acatttgccc cctttttcca gtggctgctc agccactacg cctggagggg 660gtccctgctg ctggtgtctg ccctctccct ccacctagtg gcctgtggtg ctctcctccg 720cccaccctcc ctggctgagg accctgctgt gggtggtccc agggcccaac tcacctctct 780cctccatcat ggccccttcc tccgttacac tgttgccctc accctgatca acactggcta 840cttcattccc tacctccacc tggtggccca tctccaggac ctggattggg acccactacc 900tgctgccttc ctactctcag ttgttgctat ttctgacctc gtggggcgtg tggtctccgg 960atggctggga gatgcagtcc cagggcctgt gacacgactc ctgatgctct ggaccacctt 1020gactggggtg tcactagccc tgttccctgt agctcaggct cccacagccc tggtggctct 1080ggctgtggcc tacggcttca catcaggggc tctggcccca ctggccttct ctgtgctgcc 1140tgaactaata gggactagaa ggatttactg tggcctggga ctgttgcaga tgatagagag 1200catcgggggg ctgctggggc ctcctctctc aggctacctc cgggatgtga caggcaacta 1260cacggcttct tttgtggtgg ctggggcctt ccttctttca gggagtggca ttctcctcac 1320cctgccccac ttcttctgct tctcaactac tacctccggg ccccaggacc ttgtaacaga 1380agcactagat actaaagttc ccctacccaa ggagggactg gaagaggact gaactccaca 1440gagtcaggcc cagaaagcca aagcttgaca gctccaggtc ttctcttgcc acgtcttggt 1500ctccacagaa ccacagtgcc 1520 44 3950 DNA Homo sapiens misc_feature IncyteID No 1442166CB1 44 gccagcctgt tctgttgccc tggctcttcc tagtccaggctgccatggcg gcgctcaggg 60 cttaccggaa gtaaaacttc ggaagtgagg cgttcctctgcccggaagtg agcgcggcgc 120 taggaaagat ggcggcagcg gcggcggtgg gcaacgcggtgccctgcggg gcccggcctt 180 gcggggtccg gcctgacggg cagcccaagc ccgggccgcagccgcgcgcg ctccttgccg 240 ccgggccggc gctcatagcg aacggtgacg agctggtggctgccgtgtgg ccgtaccggc 300 ggttggcgct gttgcggcgc ctcacggtgc tgccattcgccgggctgctt tacccggcct 360 ggttgggtgc cgcagccgct ggctgctggg gctggggcagcagttgggtg cagatccccg 420 aagctgcgct gctcgtgctt gccaccatct gcctcgcgcacgcgctcact gtcctctcgg 480 ggcattggtc tgtgcacgcg cattgcgcgc tcacctgcaccccggagtac gaccccagca 540 aagcgacctt tgtgaaggtg gtgccaaccc ccaacaatggctccacggag ctcgtggccc 600 tgcaccgcaa tgagggcgaa gacgggcttg aggtgctgtccttcgaattc cagaagatca 660 agtattccta cgatgccctg gagaagaagc agtttctccccgtggccttt cctgtgggaa 720 acgccttctc atactatcag agcaacagag gcttccaggaagactcagag atccgagcag 780 ctgagaagaa atttgggagc aacaaggccg agatggtggtgcctgacttc tcggagcttt 840 tcaaggagag agccacagcc cccttctttg tatttcaggtgttctgtgtg gggctctggt 900 gcctggatga gtactggtac tacagcgtct ttacgctatccatgctggtg gcgttcgagg 960 cctcgctggt gcagcagcag atgcggaaca tgtcggagatccggaagatg ggcaacaagc 1020 cccacatgat ccaggtctac cgaagccgca agtggaggcccattgccagt gatgagatcg 1080 taccagggga catcgtctcc atcggccgct ccccacaggagaacctggtg ccatgtgacg 1140 tgcttctgct gcgaggccgc tgcatcgtag acgaggccatgctcacgggg gagtccgtgc 1200 cacagatgaa ggagcccatc gaagacctca gcccagaccgggtgctggac ctccaggctg 1260 attcccggct gcacgtcatc ttcgggggca ccaaggtggtgcagcacatc cccccacaga 1320 aagccaccac gggcctgaag ccggttgaca gcgggtgcgtggcctacgtc ctgcggaccg 1380 gattcaacac atcccagggc aagctgctgc gcaccatcctcttcggggtc aagagggtga 1440 ctgcgaacaa cctggagacc ttcatcttca tcctcttcctcctggtgttt gccatcgctg 1500 cagctgccta tgtatggatt gaaggtacca aggaccccagccggaaccgc tacaagctgt 1560 ttctggagtg caccctgatc ctcacctcgg tcgtgcctcctgagctgccc atcgagctgt 1620 ccctggccgt caacacctcc ctcatcgccc tggccaagctctacatgtac tgcacagagc 1680 ccttccggat cccctttgct ggcaaggtcg aggtgtgctgctttgacaag acggggacgt 1740 tgaccagtga cagcctggtg gtgcgcggtg tggccgggctgagagacggg aaggaggtga 1800 ccccagtgtc cagcatccct gtagaaacac accgggccctggcctcgtgc cactcgctca 1860 tgcagctgga cgacggcacc ctcgtgggtg accctctagagaaggccatg ctgacggccg 1920 tggactggac gctgaccaaa gatgagaaag tattcccccgaagtattaaa actcaggggc 1980 tgaaaattca ccagcgcttt cattttgcca gtgccctgaagcgaatgtcc gtgcttgcct 2040 cgtatgagaa gctgggctcc accgacctct gctacatcgcggccgtgaag ggggcccccg 2100 aaactctgca ctccatgttc tcccagtgcc cgcccgactaccaccacatc cacaccgaga 2160 tctcccggga aggagcccgc gtcctggcgc tggggtacaaggagctggga cacctcactc 2220 accagcaggc ccgggaggtc aagcgggagg ccctggagtgcagcctcaag ttcgtcggct 2280 tcattgtggt ctcctgcccg ctcaaggctg actccaaggccgtgatccgg gagatccaga 2340 atgcgtccca ccgggtggtc atgatcacgg gagacaacccgctcactgca tgccacgtgg 2400 cccaggagct gcacttcatt gaaaaggccc acacgctgatcctgcagcct ccctccgaga 2460 aaggccggca gtgcgagtgg cgctccattg acggcagcatcgtgctgccc ctggcccggg 2520 gctccccaaa ggcactggcc ctggagtacg cactgtgcctcacaggcgac ggcttggccc 2580 acctgcaggc caccgacccc cagcagctgc tccgcctcatcccccatgtg caggtgttcg 2640 cccgtgtggc tcccaagcag aaggagtttg tcatcaccagcctgaaggag ctgggctacg 2700 tgaccctcat gtgtggggat ggcaccaacg acgtgggcgccctgaagcat gctgacgtgg 2760 gtgtggcgct cttggccaat gcccctgagc gggttgtcgagcggcgacgg cggccccggg 2820 acagcccaac cctgagcaac agtggcatca gagccacctccaggacagcc aagcagcggt 2880 cggggctccc tccctccgag gagcagccaa cctcccagagggaccgcctg agccaggtgc 2940 tgcgagacct cgaggacgag agtacgccca ttgtgaaactgggggatgcc agcatcgcag 3000 cacccttcac ctccaagctc tcatccatcc agtgcatctgccacgtgatc aagcagggcc 3060 gctgcacgct ggtgaccacg ctacagatgt tcaagatcctggcgctcaat gccctcatcc 3120 tggcctacag ccagagcgtc ctctacctgg agggagtcaagttcagtgac ttccaggcca 3180 ccctacaggg gctgctgctg gccggctgct tcctcttcatctcccgttcc aagcccctca 3240 agaccctctc ccgagaacgg cccctgccca acatcttcaacctgtacacc atcctcaccg 3300 tcatgctcca gttctttgtg cacttcctga gccttgtctacctgtaccgt gaggcccagg 3360 cccggagccc cgagaagcag gagcagttcg tggacttgtacaaggagttt gagccaagcc 3420 tggtcaacag caccgtctac atcatggcca tggccatgcagatggccacc ttcgccatca 3480 attacaaagg cccgcccttc atggagagcc tgcccgagaacaagcccctg gtgtggagtc 3540 tggcagtttc actcctggcc atcattggcc tgctcctcggctcctcgccc gacttcaaca 3600 gccagtttgg cctcgtggac atccctgtgg aggtcctgctcctggacttc tgcctggcgc 3660 tcctggccga ccgcgtcctg cagttcttcc tggggaccccgaagctgaaa gtgccttcct 3720 gagatggcag tgctggtacc cactgcccac cctggctgccgctgggcggg aaccccaaca 3780 gggccccggg agggaaccct gcccccaacc ccccacagcaaggctgtaca gtctcgccct 3840 tggaagactg agctgggacc cccacagcca tccgctggcttggccagcag aaccagcccc 3900 aagccagcac ctttggtaaa taaagcagca tctgagattttaaaaaaaaa 3950 45 5540 DNA Homo sapiens misc_feature Incyte ID No2311751CB1 45 tctacttcct ctacggcttc gtctggatcc aggacatgat ggagcgcgccatcatcgaca 60 cttttgtggg gcacgacgtg gtggagccag gcagctacgt gcagatgttcccctacccct 120 gctacacacg cgatgacttc ctgtttgtca ttgagcacat gatgccgctgtgcatggtga 180 tctcctgggt ctactccgtg gccatgacca tccagcacat cgtggcggagaaggagcacc 240 ggctcaagga ggtgatgaag accatgggcc tgaacaacgc ggtgcactgggtggcctggt 300 tcatcaccgg ctttgtgcag ctgtccatct ccgtgacagc actcaccgccatcctgaagt 360 acggccaggt gcttatgcac agccacgtgg tcatcatctg gctcttcctggcagtctacg 420 cggtggccac catcatgttc tgcttcctgg tgtctgtgct gtactccaaggccaagctgg 480 cctcggcctg cggtggcatc atctacttcc tgagctacgt gccctacatgtacgtggcga 540 tccgagagga ggtggcgcat gataagatca cggccttcga gaagtgcatcgcgtccctca 600 tgtccacgac ggcctttggt ctgggctcta agtacttcgc gctgtatgaggtggccggcg 660 tgggcatcca gtggcacacc ttcagccagt ccccggtgga gggggacgacttcaacttgc 720 tcctggctgt caccatgctg atggtggacg ccgtggtcta tggcatcctcacgtggtaca 780 ttgaggctgt gcacccaggc atgtacgggc tgccccggcc ctggtacttcccactgcaga 840 agtcctactg gctgggcagt gggcggacag aagcctggga gtggagctggccgtgggcac 900 gcaccccccg cctcagtgtc atggaggagg accaggcctg tgccatggagagccggcgct 960 ttgaggagac ccgtggcatg gaggaggagc ccacccacct gcctctggttgtctgcgtgg 1020 acaaactcac caaggtctac aaggacgaca agaagctggc cctgaacaagctgagcctga 1080 acctctacga gaaccaggtg gtctccttct tgggccacaa cggggcgggcaagaccacca 1140 ccatgtccat cctgaccggc ctgttccctc caacgtcggg ttccgccaccatctacgggc 1200 acgacatccg cacggagatg gatgagatcc gcaagaacct gggcatgtgcccgcagcaca 1260 atgtgctctt tgaccggctc acggtggagg aacacctctg gttctactcacggctcaaga 1320 gcatggctca ggaggagatc cgcagagaga tggacaagat gatcgaggacctggagctct 1380 ccaacaaacg gcactcactg gtgcagacat tgtcgggtgg catgaagcgcaagctgtccg 1440 tggccatcgc cttcgtgggc ggctctcgcg ccatcatcct ggacgagcccacggcgggcg 1500 tggaccccta cgcgcgccgc gccatctggg acctcatcct gaagtacaagccaggccgca 1560 ccatccttct gtccacccac cacatggatg aggctgacct gcttggggaccgcattgcca 1620 tcatctccca tgggaagctc aagtgctgcg gctccccgct cttcctcaagggcacctatg 1680 gcgacgggta ccgcctcacg ctggtcaagc ggcccgccga gccggggggcccccaagagc 1740 cagggctggc atccagcccc ccaggtcggg ccccgctgag cagctgctccgagctccagg 1800 tgtcccagtt catccgcaag catgtggcct cctgcctgct ggtctcagacacaagcacgg 1860 agctctccta catcctgccc agcgaggccg ccaagaaggg ggctttcgagcgcctcttcc 1920 agcacctgga gcgcagcctg gatgcactgc acctcagcag cttcgggctgatggacacga 1980 ccctggagga agtgttcctc aaggtgtcgg aggaggatca gtcgctggagaacagtgagg 2040 ccgatgtgaa ggagtccagg aaggatgtgc tccctggggc ggagggcccggcgtctgggg 2100 agggtcacgc tggcaatctg gcccggtgct cggagctgac ccagtcgcaggcatcgctgc 2160 agtcggcgtc atctgtgggc tctgcccgtg gcgacgaggg agctggctacaccgacgtct 2220 atggcgacta ccgccccctc tttgataacc cacaggaccc agacaatgtcagcctgcaag 2280 aggtggaggc agaggccctg tcgagggtcg gccagggcag ccgcaagctggacggcgggt 2340 ggctgaaggt gcgccagttc cacgggctgc tggtcaaacg cttccactgcgcccgccgca 2400 actccaaggc actcttctcc cagatcttgc tgccagcctt cttcgtctgcgtggccatga 2460 ccgtggccct gtccgtcccg gagattggtg atctgccccc gctggtcctgtcaccttccc 2520 agtaccacaa ctacacccag ccccgtggca atttcatccc ctacgccaacgaggagcgcc 2580 gcgagtaccg gctgcggcta tcgcccgacg ccagccccca gcagctcgtgagcacgttcc 2640 ggctgccgtc gggggtgggt gccacctgcg tgctcaagtc tcccgccaacggctcgctgg 2700 ggcccacgtt gaacctgagc agcggggagt cgcgcctgct ggcggctcggttcttcgaca 2760 gcatgtgtct ggagtccttc acacaggggc tgccactgtc caatttcgtgccacccccac 2820 cctcgcccgc cccatctgac tcgccagcgt ccccggatga ggacctgcaggcctggaacg 2880 tctccctgcc gcccaccgct gggccagaaa tgtggacgtc ggcaccctccctgccgcgcc 2940 tggtacggga gcccgtccgc tgcacctgct ctgcgcaggg caccggcttctcctgcccca 3000 gcagtgtggg cgggcacccg ccccagatgc gggtggtcac aggcgacatcctgaccgaca 3060 tcaccggcca caatgtctct gagtacctgc tcttcacctc cgaccgcttccgactgcacc 3120 ggtatggggc catcaccttt ggaaacgtcc tgaagtccat cccagcctcatttggcacca 3180 gggccccacc catggtgcgg aagatcgcgg tgcgcagggc tgcccaggttttctacaaca 3240 acaagggcta tcacagcatg cccacctacc tcaacagcct caacaacgccatcctgcgtg 3300 ccaacctgcc caagagcaag ggcaacccgg cggcttacgg catcaccgtcaccaaccacc 3360 ccatgaataa gaccagcgcc agcctctccc tggattacct gctgcagggcacggatgtcg 3420 tcatcgccat cttcatcatc gtggccatgt ccttcgtgcc ggccagcttcgttgtcttcc 3480 tcgtggccga gaagtccacc aaggccaagc atctgcagtt tgtcagcggctgcaacccca 3540 tcatctactg gctggcgaac tacgtgtggg acatgctcaa ctacctggtccccgctacct 3600 gctgtgtcat catcctgttt gtgttcgacc tgccggccta cacgtcgcccaccaacttcc 3660 ctgccgtcct ctccctcttc ctgctctatg ggtggtccat cacgcccatcatgtacccgg 3720 cctccttctg gttcgaggtc cccagctccg cctacgtgtt cctcattgtcatcaatctct 3780 tcatcggcat caccgccacc gtggccacct tcctgctaca gctcttcgagcacgacaagg 3840 acctgaaggt tgtcaacagt tacctgaaaa gctgcttcct cattttccccaactacaacc 3900 tgggccacgg gctcatggag atggcctaca acgagtacat caacgagtactacgccaaga 3960 ttggccagtt tgacaagatg aagtccccgt tcgagtggga cattgtcacccgcggactgg 4020 tggccatggc ggttgagggc gtcgtgggct tcctcctgac catcatgtgccagtacaact 4080 tcctgcggcg gccacagcgc atgcctgtgt ctaccaagcc tgtggaggatgatgtggacg 4140 tggccagtga gcggcagcga gtgctccggg gagacgccga caatgacatggtcaagattg 4200 agaacctgac caaggtctac aagtcccgga agattggccg tatcctggccgttgaccgcc 4260 tgtgcctggg tgtgcgtcct ggcgagtgct tcgggctcct gggcgtcaacggtgcgggca 4320 agaccagcac cttcaagatg ctgaccggcg acgagagcac gacggggggcgaggccttcg 4380 tcaatggaca cagcgtgctg aaggagctgc tccaggtgca gcagagcctcggctactgcc 4440 cgcagtgtga cgcgctgttc gacgagctca cggcccggga gcacctgcagctgtacacgc 4500 ggctgcgtgg gatctcctgg aaggacgagg cccgggtggt gaagtgggctctggagaagc 4560 tggagctgac caagtacgca gacaagccgg ctggcaccta cagcggcggcaacaagcgga 4620 agctctccac ggccatcgcc ctcattgggt acccagcctt catcttcctggacgagccca 4680 ccacaggcat ggaccccaag gcccggcgct tcctctggaa cctcatcctcgacctcatca 4740 agacagggcg ttcagtggtg ctgacatcac acagcatgga ggagtgcgaggcgctgtgca 4800 cgcggctggc catcatggtg aacggtcgcc tgcggtgcct gggcagcatccagcacctga 4860 agaaccggtt tggagatggc tacatgatca cggtgcggac caagagcagccagagtgtga 4920 aggacgtggt gcggttcttc aaccgcaact tcccggaagc catgctcaaggagcggcacc 4980 acacaaaggt gcagtaccag ctcaagtcgg agcacatctc gctggcccaggtgttcagca 5040 agatggagca ggtgtctggc gtgctgggca tcgaggacta ctcggtcagccagaccacac 5100 tggacaatgt gttcgtgaac tttgccaaga agcagagtga caacctggagcagcaggaga 5160 cggagccgcc atccgcactg cagtcccctc tcggctgctt gctcagcctgctccggcccc 5220 ggtctgcccc cacggagctc cgggcacttg tggcagacga gcccgaggacctggacacgg 5280 aggacgaggg cctcatcagc ttcgaggagg agcgggccca gctgtccttcaacacggaca 5340 cgctctgctg accacccaga gctgggccag ggaggacacg ctccactgaccacccagagc 5400 tgggccaggg actcaacaat ggggacagaa gtcccccagt gcctgccagggcctggagtg 5460 gaggttcagg accaaggggc ttctggtcct ccagcccctg tactcggccatgtcctgcgg 5520 tcactgcggt tgccggccct 5540 46 2074 DNA Homo sapiensmisc_feature Incyte ID No 7472537CB1 46 ggaatcacag tgcctaggca tataataaatattcgttgaa ttaataaaat catctgatta 60 tggtatggta gtagttcaga aaattctgtcatgaccctgt actctttctt tggaagggct 120 ctaaatggga acaacaatat agtatgtagtctctctgcat agctaatgtg cagcaaagca 180 gggcaatgta ggtatacaac caatctatttttcaactcag aaacatcaca tcatttccat 240 tcctttataa ccatccttct tccatcccaaagtatagttt gtcaacctgg aactcaaaca 300 ttgtatggtc tggaatgacc gtacagtgtgaaggaggaaa agaaaattgg ggtgtcttat 360 ttcccctcct ctgattcagt tacttagatcacctgaaaca tacatatgat tcagagcata 420 tatttagatg ttttcacttt cttatttgtgtgtgtgtgtg ttcagtcaat ttgctaatga 480 agacactgaa agtcagaaat tcctgacaaatggatttttg gggaaaaaga agctggcaga 540 tcccttcttt ttcaagcatc ccggaaccacttcctttgga atgtcttcat ttaacctgag 600 taatgccatc atgggcagtg ggatcctgggcttgtcctat gccatggcca acacagggat 660 catacttttt atgttcatgc tgcttgctgtggcaatatta tcactgtatt cagttcacct 720 tttattaaaa acatctttga ttgtagggtctttgatttat gaaaaattag gagaaaaggc 780 atttggatgg ccgggaaaaa ttggagcttttgtttccatt acaatgcaga acattggagc 840 aatgtcaagc tacctcttta tcattaaatatgaactacct gaagtaatca gagcattcat 900 gggacttgaa gaaacttcta gagaatggtacctcaatggc aactacctca tcatatttgt 960 gtctgttgga attattcttc cactttcgctccttaaaaat ctaggttatc ttggctatac 1020 cagtggattt tctcttacct gcatggtgttttttgttagt gtggtgattt acaagaaatt 1080 ccaaataccc tgccctctac ctgagaaccaggccaagggc tctcttcatg acagtggagt 1140 agaatatgaa gctcatagtg atgacaagtgtgaacccaaa tactttgtat tcaactccca 1200 gacggcctat gcaattccta tcctagtatttgcttttgta tgccaccctg aggtccttcc 1260 catctacagt gaacttaaag atcggtcccggagaaaaatg caaacggtgt caaatatttc 1320 catcacgggg atgcttgtca tgtacctgcttgccgccctc tttggttacc taaccttcta 1380 tggtagggtt gaagatgaat tacttcatgcctacagcaaa gtgtatacat tagacatccc 1440 ccttctcatg gttcgcctgg cagtccttgtggcagtaaca ctaactgtgc ccattgtcct 1500 cttcccagtt cgtacatcag tgatcacactgttatttccc aaacgaccct tcagctggat 1560 acgacatttc ctgattgcag ctgtgcttattgcacttaat aatgttctgg tcatccttgt 1620 gccaactata aaatacatct tcggattcataggggcttct tctgccacta tgctgatttt 1680 tattcttcca gcagtttttt atcttaaacttgtcaagaaa gaaactttta ggtcaccccc 1740 tgaattacag gctttaattt tccttgtggttggaatattc ttcatgattg gaagcatggc 1800 actcattata attgactgga tttatgatcctccaaattcc aagcatcact aacacaagga 1860 aaaatactnt ctttttctat tggaaatggttacaagtnat actccaaaag atatttgaat 1920 tatcttgatt ggaatgttat tcataggaaataacaggaag attccaaaga cgtttaccag 1980 taatatcncc aggcacctgn cagaagagggaaaatcactg tttttgtcaa ggatggttgt 2040 gtatgtgttt taaaataaaa cctgtggtgcacat 2074 47 2259 DNA Homo sapiens misc_feature Incyte ID No 7472546CB147 atggaatacc aggcgtccga ggtgatcggg cagcgtcagt cttcagccac taagccagga 60agatctggga aggagtcagt cacagagccc tgggccagag ttccaggggc tctgggagtg 120gctgccaggc agatgcaccc caagtcaata atcacattca gagagataaa tggggagtac 180actggggctg tggattttcc caggctagga gtccgtgctt ctgaggaaac agcgctcaga 240gagctgaaga tgagcaagga gctggcagca atggggcctg gagcttcagg ggacggggtc 300aggactgaga cagctccaca catagcactg gactccagag ttggtctgca cgcctacgac 360atcagcgtgg tggtcatcta ctttgtcttc gtcattgctg tggggatctg gtcgtccatc 420cgtgcaagtc gagggaccat tggcggctat ttcctggccg ggaggtccat gagctggtgg 480ccaattggag catctctgat gtccagcaat gtgggcagtg gcttgttcat cggcctggct 540gggacagggg ctgccggagg ccttgccgta ggtggcttcg agtggaacgc aacctggctg 600ctcctggccc ttggctgggt cttcgtccct gtgtacatcg cagcaggtgt ggtcacaatg 660ccgcagtatc tgaagaagcg atttgggggc cagaggatcc aggtgtacat gtctgtcctg 720tctctcatcc tctacatctt caccaagatc tcgactgaca tcttctctgg agccctcttc 780atccagatgg cattgggctg gaacctgtac ctctccacag ggatcctgct ggtggtgact 840gccgtctaca ccattgcagg tggcctcatg gccgtgatct acacagatgc tctgcagacg 900gtgatcatgg tagggggagc cctggtcctc atgtttctgg gctttcagga cgtgggctgg 960tacccaggcc tggagcagcg gtacaggcag gccatcccta atgtcacagt ccccaacacc 1020acctgtcacc tcccacggcc cgatgctttc cacattcttc gggaccctgt gagcggggac 1080atcccttggc caggtctcat tttcgggctc acagtgctgg ccacctggtg ttggtgcaca 1140gaccaggtca ttgtgcagcg gtctctctcg gccaagagtc tgtctcatgc caagggaggc 1200tccgtgctgg ggggctacct gaagatcctc cccatgttct tcatcgtcat gcctggcatg 1260atcagccggg ccctgttccc agacgaggtg ggctgcgtgg accctgatgt ctgccaaaga 1320atctgtgggg cccgagtggg atgttccaac attgcctacc ctaagttggt catggccctc 1380atgcctgttg gtctgcgggg gctgatgatt gccgtgatca tggccgctct catgagctca 1440ctcacctcca tcttcaacag cagcagcacc ctgttcacca ttgatgtgtg gcagcgcttc 1500cgcaggaagt caacagagca ggagctgatg gtggtgggca gagtgtttgt ggtgttcctg 1560gttgtcatca gcatcctctg gatccccatc atccaaagct ccaacagtgg gcagctcttc 1620gactacatcc aggctgtcac cagttacctg gccccaccca tcaccgctct cttcctgctg 1680gccatcttct gcaagagggt cacagagccc ggagctttct ggggcctcgt gtttggcctg 1740ggagtggggc ttctgcgtat gatcctggag ttctcatacc cagcgccagc ctgtggggag 1800gtggaccgga ggccagcagt gctgaaggac ttccactacc tgtactttgc aatcctcctc 1860tgcgggctca ctgccatcgt cattgtcatt ctcacacgcc tcacatggtg gactcggaac 1920tgccccctct ctgagctgga gaaggaggcc cacgagagca caccggagat atccgagagg 1980ccagccgggg agtgccctgc aggaggtgga gcggcagaga actcgagcct gggccaggag 2040cagcctgaag ccccaagcag gtcctgggga aagttgctct ggagctggtt ctgtgggctc 2100tctggaacac cggagcaggc cctgagccca gcagagaagg ctgcgctaga acagaagctg 2160acaagcattg aggaggagcc actctggaga catgtctgca acatcaatgc tgtccttttg 2220ctggccatca acatcttcct ctggggctat tttgcgtga 2259 48 2439 DNA Homo sapiensmisc_feature Incyte ID No 7474202CB1 48 ggctctgtga gaggagggcc agttcagccgcagcaggagg actgacaggg gcctgatgga 60 ggagttggtg gggctgcgtg agggcttctcaggggaccct gtgactctgc aggagctgtg 120 gggcccctgt ccccacatcc gccgagccatccaaggtggc ctggagtggc taaagcagaa 180 ggtgttccgc ctgggagaag actggtacttcctgatgacc ctcggggtgc tcatggccct 240 ggtcagctat gccatgaact ttgccatcgggtgtgtggtc cgaggcttct cccagagcat 300 cacgccctcc tctggaggtt ctggaatcccggagctgaag accatgttgg cgggtgtgat 360 cttggaggac tacctggata tcaagaactttggggccaag gtggtgggcc tctcctgcac 420 cctggccacc ggcagcaccc tgttcctgggcaaagtgggc cctttcgtgc acctgtctgt 480 aatgatcgct gcctacctgg gccgtgtgcgcaccacgacc atcggggagc ctgagaacaa 540 gagcaagcaa aacgaaatgc tggtggcagcggcggcagtg ggcgtggcca cagtctttgc 600 agctcccttc agcggcgtcc tgttcagcatcgaggtcatg tcttcccact tctctgtccg 660 ggattactgg aggggcttct ttgcggccacctgcggggcc ttcatattcc ggctcctggc 720 agtcttcaac agcgagcagg agaccatcacctccctctac aagaccagtt tccgggtgga 780 cgttcccttc gacctgcctg agatcttcttttttgtggcg ctgggtggca tctgcggcgt 840 cctgagctgt gcttacctct tctgtcagcgaaccttcctc agcttcatca agaccaatcg 900 gtacagctcc aaactgctgg ctactagcaagcctgtgtac tccgctctgg ccaccttgct 960 tctcgcctcc atcacctacc cgcctggtgtgggccacttc ctagcttctc ggctgtccat 1020 gaagcagcat ctggactcgc tgttcgacaaccactcctgg gcgctgatga cccagaactc 1080 cagcccaccc tggcccgagg agctcgacccccagcacctt tggtgggaat ggtaccaccc 1140 gcggttcacc atctttggga cccttgccttcttcctggtt atgaagttct ggatgctgat 1200 tctggccacc accatcccca tgcctgccgggtacttcatg cccatcttta tccttggagc 1260 tgccatcggg cgcctcttgg gagaggctcttgccgtcgcc ttccctgagg gcattgtgac 1320 tggaggggtt accaatccca tcatgcccggggggtatgct ctggcagggg ctgcagcctt 1380 ctcaggggct gtgacccaca ccatctccacggcgctgctg gcctttgagc tgaccggcca 1440 gatagtgcat gcactgcccg tgctgatggcggtgctggca gccaacgcca ttgcacagag 1500 ctgccagccc tccttctatg atggcaccatcattgtcaag aagctgccat acctgccacg 1560 gattctgggc cgcaacatcg gctcccaccatgtgagggtg gagcacttca tgaaccacag 1620 catcaccaca ctggccaagg acacgccgctggaggaggtg gtcaaggttg tgacctccac 1680 agacgtgacc gagtatcccc tggtggagagcacagagtcc cagatcctgg taggcatcgt 1740 gcagagggcc cagctggtgc aggccctccaggctgagcct ccttccaggg ctccaggaca 1800 ccagtgtctc caggacatct tggccaggggctgccccacg gaaccagtga ccctgacgct 1860 attctcagag accaccttgc accaggcacaaaacctcttt aagctgttga accttcagtc 1920 cctcttcgtg acatcgcggg gcagagctgtgggctgcgtg tcctgggtgg agatgaagaa 1980 agcaatttcc aacctgacaa atccgccagctccaaagtga gccggcccag caagatgaaa 2040 cagggcaccc cagctgacct ggtactgaggttgggctgag accctgcttc tcttccccca 2100 tcaccacctg cccctccctc cagcccagctccattctttg gcataacagg caactctaac 2160 ctagcccaga agaggatggc tcatcctgggtgggacgatg gctcctgcct tgaaagacaa 2220 aaatcccacc ttgggcagag ctgagtgtgagaagatggaa aaccagtatc tgccaggtgc 2280 tcagtgactg gccatcacat taatgaatgacgagattgga gtacactgtc accaagggca 2340 ggcaaagatg ccctctgggg ttgtctggttcccagtgaga ggctcctgag aaaaataaag 2400 ctggttccca gagctgctgt ccatccctcaaaaaaaaaa 2439 49 2762 DNA Homo sapiens misc_feature Incyte ID No7476280CB1 49 atggacccca tcacgcctaa ctggactgag atcgtgaaca ggaagctcagcttcccacct 60 ccactcctgg atgccatcca ggagggccga ctgggctttg tgcagcagctgctggagtca 120 gaggttgagg ccgcgagcag tgggccaggc tggcccctgt ggaatgtggaagaggctgag 180 gaccgctgct ggagggaggc actcaacctg gccatccgcc tgggccatgaggccctcacc 240 gatgtgctgt tggccagtgt caagtttgac ttccgccaga tccatgaggccctgctagtg 300 gcagtggaca caaaccaggc agtggtgcgt cgcctgccgg cccggctggaacgggagaag 360 ggtcgcaaag tagacaccag gtctttctca ctggctttct ttgactcatcaattgatggc 420 tcccgctttg cacctggtgt gactcccctc ccccaggcct gccagaaggacctgtatgag 480 atagcacagc tgctcatgga acagggccac accattgccc ggccccacccggtctcctgt 540 gcctgcctcg agtgcagcaa cgcccgccgc tatgacctgc tgaaactctctctgtcccgc 600 atcaacacct accttggcat cgccagcagg gcccacctct cactggccagtgaggatgcc 660 atgctggctg ccttccagct tagccgtgag ctcaggcgcc ttgcacgcaaggagcctgaa 720 tttaagcctg agtacattgc tctggagtca ctgagccagg actatggctttcagctgctg 780 ggcatgtgct ggaaccagag tgaggtcact gcagtgctca acgacctggccgaggacagc 840 gagactgagc ccgaggctga aggcctgggc ctggcctttg aggaaggcatccccaacctg 900 gtgaggctgc gactggctgt caactacaac cagaagcggt tcgtagcacacctcatctgc 960 cagcaagtcc tgtcctccat ctggtgtggg aacctggctg gttggcggggaagcaccacc 1020 agctggaagc tctttgctac cttcctcatc ttcctcacca tgcccttcctctgccttggc 1080 tactggctga caccaaagtc ccagctgggc cacctgctaa agatcccagtactgaagttc 1140 ctgctgcact ctgcctccta tctgtggttc ctcatcttcc tgctgggagagtccctggtc 1200 atggagacac agctgagcac cttccgtggc cgcagccaga gtgtctgggagacttcacta 1260 cacatgattt gtgtcacagg cttcctgtgg tttgagtgca aggaagtgtggattgagggc 1320 ctgcgcagtt acctcctgga ctggtggaac ttcctggata tggtcgtcctgtccctgtac 1380 ctggcagcct tcgcactgcg cctcctcctg gctgggcttg cccccatgcactgccgggac 1440 gcctcccaag cggctgcctg ccactatttc accatggctg aaagaagcgagtggcacacc 1500 gaggatcccc agttcttggc tgaggtgctc ttcactgcca ccagcatgctcagcttcacc 1560 cgcctggcct acattctgcc ggcccacgag tcgctgggca ctctgcagatttccattggc 1620 aagatgattg aagacatgat ccggtttatg ttcatcctca tgatcatcctgaccgccttc 1680 ctctgtggcc tcaacaacat ctatgtgccc taccagaaga cagagtggctgggcaagagt 1740 ttcaatgaga cgtttcagtt tctgttctgg accatgttcg gtatggaagagcacagcgtg 1800 gtggacgtgc ctcagtttct ggtgcccgag tttgcaggcc gggccctctatggcatcttt 1860 accatcatca tggtcattgt gctgctcaac atgctcattg ctatgatcaccaactccttc 1920 cagaagattg aggatgatgc tgacgtggag tggacgtttg ctcgctccaagctgtatctg 1980 ttctacttcc gagagggcct gacactgcct gtgcccttca acatcctgccctcctcgaag 2040 gctgtcttct accttctcag gagaatttgc cagttcattt gctgttgctgttcctgctgc 2100 aaaaccaaga agccagacta tcccccgatc cctacttttg tgaatcccagggcaggggct 2160 gtgcctgggg agggagagcg tggatcctac cgccttcacg tcatcaaggccctggtacag 2220 cgctacacag agactgcccg gcgagaattc gaggagaccc ggcggaaagatctgggcaac 2280 agactcacag agctgaccaa gaccatatct cgactgcaaa gcgaggtagccggtgtgcgg 2340 agaactctgg cagagggagg gacgccccgg cctcccgacg gtgccagcgtcctcagtcac 2400 tacatcactc aagtgcacaa cagcttccag aacctggggc ctcccatccctgagacccca 2460 gagctgacag ggcctgggat tgtgaggacc caggaatcat caggaaccgggcttcaggac 2520 actggagggg tgaggactct ggcttccgga gagtctggcc cctgctccccagctcatgtg 2580 ctagttcata gggagcagga agcagagggg gctggggacc tgccccagggggaggattcg 2640 gggactgaga ggaggtcctg atacagtgga agagtccctt cttctgttgctgagcgtggt 2700 agcctaggag ggtgagggtg gggggcccct tgggaggagc ctgtgctgcttttcttgctt 2760 ca 2762 50 1897 DNA Homo sapiens misc_feature Incyte IDNo 1713377CB1 50 gcgatctaga actagtgagc tgcaggctgg catggctggg gggatgtcagcggagtgccc 60 tgagcctggg ccaggaggtc tgcagggcca gtccccaggg ccaggcaggcagtgtccccc 120 tcccatcacg cccacctcct ggagcctgcc cccgtggagg gcctacgtggctgccgccgt 180 cctctgctac atcaacctcc tgaattacat gaactggttc atcattgcaggagtgctgct 240 ggatatacag gaggttttcc agatcagtga caaccatgct ggtttgcttcagactgtctt 300 cgttagctgc ctgctgctgt ctgcacctgt gtttggctac ctgggcgaccgacatagccg 360 caaggctacc atgagcttcg gtatcttgct gtggtcagga gctggcctctctagctcctt 420 catctccccc cggtattctt ggctcttctt cctgtcccgg ggcatcgtgggcactggctc 480 ggccagctac tccaccatcg cgcccaccgt cctgggcgac ctcttcgtgagggaccagcg 540 cacccgcgtg ctggctgtct tctacatctt tatccccgtt ggaagtggtctgggctacgt 600 gctggggtcg gctgtgacga tgctgactgg gaactggcgc tgggccctccgagtcatgcc 660 ctgcctggag gccgtggcct tgatcctgct tatcctgctg gttccagacccaccccgggg 720 agctgccgag acacaggggg agggggccgt gggaggcttc agaagcagctggtgtgagga 780 cgtcagatac ctggggaaaa actggagttt tgtgtggtcg accctcggagtgaccgccat 840 ggcctttgtg actggagccc tggggttctg ggcccccaag tttctgctcgaggcacgcgt 900 ggttcacggg ctgcagcctc cctgcttcca ggagccgtgc agcaaccccgacagcctgat 960 ttttggggca ctgaccatca tgaccggcgt cattggggtc atcttgggggcagaagcttc 1020 gaggaggtac aagaaagtca ttccaggagc tgagcccctc atctgcgcctccagcctgct 1080 tgccacagcc ccctgcctct acctggctct cgtcctggcc ccgaccaccctgctggcctc 1140 ctatgtgttc ctgggccttg gggagctgct tctgtcctgc aactgggcagtggttgccga 1200 catcctgctg tctgtggtgg tgcccagatg ccgggggacg gcagaggcacttcagatcac 1260 ggtgggccac atcctgggag acgctggcag cccctatctc acaggacttatctctagtgt 1320 cctgcgggcc aggcgccctg actcctatct gcagcgcttc cgcagcctgcagcagagctt 1380 cctgtgctgc gcctttgtca tcgccctggg gggcggctgc ttcctgctgactgcgctgta 1440 cctggagaga gacgagaccc gggcctggca gcctgtcaca gggaccccagacagcaatga 1500 tgtggacagc aacgacctgg agagacaagg cctactttcg ggcgctggcgcctctacaga 1560 ggagccctga ggtccctgcc tacactcgtc ctgcctgcaa gcctcccgttggtccccaca 1620 gcagcagtgc ctcggttcct ctttggctgt cctcggggac tccggctgaggcacatctgc 1680 cacttttgaa ttcccggctg gagagctggc aggaccctgt ggctgggctgggaatggagc 1740 tgtcagcact ctgcgtggga ggcctgggcc tgtgcctgca tcccgctcaaggctgcccca 1800 gcctggggtc tccagcctgg ctgctgctgg gccctgaata aagagaggccagtacaaagc 1860 ccatggattt tgggcctgta aaaaaaaaaa aaaaaaa 1897 51 2361DNA Homo sapiens misc_feature Incyte ID No 5842557CB1 51 gatgatggcagacaggagag ctgactactt tcagaacctg cctgagtctc tgacttccct 60 tcctggtgcttctgaccacg tccaacaacc ccgatgtgat gattcctgcg tattccaaga 120 accgggcctatgccatcttc ttcatagtct tcactgtgat aggaagcctg tttctgatga 180 acctgctgacagccatcatc tacagtcagt tccggggcta cctgatgaaa tctctccaga 240 cctcgctgtttcggaggcgg ctgggaaccc gggctgcctt tgaagtccta tcctccatgg 300 tgggggagggaggagccttc cctcaggcag ttggggtgaa gccccagaac ttgctgcagg 360 tgcttcagaaggtccagctg gacagctccc acaaacaggc catgatggag aaggtgcgtt 420 cctacgacagtgttctgctg tcagctgagg agtttcagaa gctcttcaac gagcttgaca 480 gaagtgtggttaaagagcac ccgccgaggc ccgagtacca gtctccgttt ctgcagagcg 540 cccagttcctcttcggccac tactactttg actacctggg gaacctcatc gccctggcaa 600 acctggtgtccatttgcgtg ttcctggtgc tggatgcaga tgtgctgcct gctgagcgtg 660 atgacttcatcctggggatt ctcaactgcg tcttcattgt gtactacctg ttggagatgc 720 tgctcaaggtctttgccctg ggcctgcgag ggtacctgtc ctaccccagc aacgtgtttg 780 acgggctcctcaccgttgtc ctgctggttt tggagatctc aactctggct gtgtaccgat 840 tgccacacccaggctggagg ccggagatgg tgggcctgct gtcgctgtgg gacatgaccc 900 gcatgctgaacatgctcatc gtgttccgct tcctgcgtat catccccagc atgaagccga 960 tggccgtggtggccagtacc gtcctgggcc tggtgcagaa catgcgtgct tttggcggga 1020 tcctggtggtggtctactac gtatttgcca tcattgggat caacttgttt agaggcgtca 1080 ttgtggctcttcctggaaac agcagcctgg cccctgccaa tggctcggcg ccctgtggga 1140 gcttcgagcagctggagtac tgggccaaca acttcgatga ctttgcggct gccctggtca 1200 ctctgtggaacttgatggtg gtgaacaact ggcaggtgtt tctggatgca tatcggcgct 1260 actcaggcccgtggtccaag atctattttg tattgtggtg gctggtgtcg tctgtcatct 1320 gggtcaacctgtttctggcc ctgattctgg agaacttcct tcacaagtgg gacccccgca 1380 gccacctgcagccccttgct gggaccccag aggccaccta ccagatgact gtggagctcc 1440 tgttcagggatattctggag gagcccgagg aggatgagct cacagagagg ctgagccagc 1500 acccgcacctgtggctgtgc aggtgacgtc cgggctgccg tcccagcagg ggcggcagga 1560 gagagaggctggcctacaca ggtgcccgtc atggaagagg cggccatgct gtggccagcc 1620 aggcaggaagagacctttcc tctgacggac cactaagctg gggacaggaa ccaagtcctt 1680 tgcgtgtggcccaacaaccg tctacagaac agctgctggt gcttcaggga ggcgccgtgc 1740 cctccgctttcttttatagc tgcttcagtg agaattccct cgtcgactcc acagggacct 1800 ttcagacaaaaatgcaagaa gcagcggcct cccctgtccc ctgcagcttc cgtggtgcct 1860 ttgctgccggcagcccttgg ggaccacagg cctgaccagg gcctgcacag gttaaccgtc 1920 agacttccggggcattcagg tggggatgct ggtggtttga catggagaga accttgactg 1980 tgttttattatttcatggct tgtatgagtg tgactgggtg tgtttcttta gggttctgat 2040 tgccagttattttcatcaat aagtcttgca aagaatggga ttgtcattct tcacttcagc 2100 acagttctagtcctgcttct ctggagtagg gttgttgagt aaggttgctt gggttgtgca 2160 tttgcacaagggcacatggc tgtgaggtgt atcctggcgg ggggctgtct acctgcagtg 2220 aggggcaccttttctgtttt gctcaaaggc atgtataagc caatgggtga ccttatttcc 2280 tgtgtcttcaggtgtgtgca ggggcctggg gtggggagtt gggggagcga gcagtgtgtg 2340 gaaggggatccactagttct a 2361 52 2032 DNA Homo sapiens misc_feature Incyte ID No7476643CB1 52 gccttggcag agtctggggt ccctggactg agccatcagc tgggtcactgagacccatgg 60 caaggaaaca aaataggaat tccaaggaac tgggcctagt tcccctcacagatgacacca 120 gccacgccag gcctccaggg ccagggaggg cactgctgga gtgtgaccacctgaggagtg 180 gggtgccagg tggaaggaga agaaaggact ggtcctgctc gctcctcgtggcctccctcg 240 cgggcgcctt cggctcctcc ttcctctacg gctacaacct gtcggtggtgaatgccccca 300 ccccgtacat caaggccttt tacaatgagt catgggaaag aaggcatggacgtccaatag 360 acccagacac tctgactttg ctctggtctg tgactgtgtc catattcgccatcggtggac 420 ttgtggggac gttaattgtg aagatgattg gaaaggttct tgggaggaagcacactttgc 480 tggccaataa tgggtttgca atttctgctg cattgctgat ggcctgctcgctccaggcag 540 gagcctttga aatgctcatc gtgggacgct tcatcatggg catagatggaggcgtcgccc 600 tcagtgtgct ccccatgtac ctcagtgaga tctcacccaa ggagatccgtggctctctgg 660 ggcaggtgac tgccatcttt atctgcattg gcgtgttcac tgggcagcttctgggcctgc 720 ccgagctgct gggaaaggag agtacctggc catacctgtt tggagtgattgtggtccctg 780 ccgttgtcca gctgctgagc cttccctttc tcccggacag cccacgctacctgctcttgg 840 agaagcacaa cgaggcaaga gctgtgaaag ccttccaaac gttcttgggtaaagcagacg 900 tttcccaaga ggtagaggag gtcctggctg agagccgcgt gcagaggagcatccgcctgg 960 tgtccgtgct ggagctgctg agagctccct acgtccgctg gcaggtggtcaccgtgattg 1020 tcaccatggc ctgctaccag ctctgtggcc tcaatgcaat ttggttctataccaacagca 1080 tctttggaaa agctgggatc cctctggcaa agatcccata cgtcaccttgagtacagggg 1140 gcatcgagac tttggctgcc gtcttctctg gtttggtcat tgagcacctgggacggagac 1200 ccctcctcat tggtggcttt gggctcatgg gcctcttctt tgggaccctcaccatcacgc 1260 tgaccctgca ggaccacgcc ccctgggtcc cctacctgag tatcgtgggcattctggcca 1320 tcatcgcctc tttctgcagt gggccaggtg gcatcccgtt catcttgactggtgagttct 1380 tccagcaatc tcagcggccg gctgccttca tcattgcagg caccgtcaactggctctcca 1440 actttgctgt tgggctcctc ttcccattca ttcagaaaag tctggacacctactgtttcc 1500 tagtctttgc tacaatttgt atcacaggtg ctatctacct gtattttgtgctgcctgaga 1560 ccaaaaacag aacctatgca gaaatcagcc aggcattttc caaaaggaacaaagcatacc 1620 caccagaaga gaaaatcgac tcagctgtca ctgatgctca aaggaactaagacaaagatc 1680 atggagacca tcgggtgagt ctcaagactt cccccagctc tgcttggctggtctcctgct 1740 ggtattttct gtctgtagag aggaacaaga acttccattt tatcttgcttacctgcactt 1800 atgaaaagtc aaactgagtc atgctgagag ccagggaaca taggagtcagttcttctgca 1860 gcagcactca gccagttgaa ggcaatgtgg agtgatggaa ggagagcagtgatgcagtga 1920 tgctggcacc aactccttta ctatggcatc cattgtacca gctgccatacaccaggcaac 1980 ttctacactt tatctctaat catcctagaa taagtattag tttccccatctt 2032 53 2779 DNA Homo sapiens misc_feature Incyte ID No 7611651CB1 53cgcctgtggc tccgggcagg ggccgcggcc gaaagatgcc ggtccgcagg ggccacgtcg 60ctccccaaaa cacttacctg gacaccatca tccgcaagtt cgagggccaa agtcggaagt 120tcctgattgc caatgctcag atggagaact gcgccatcat ttactgcaac gacggcttct 180gcgaactctt cggctactcc cgagtggagg tgatgcagca accctgcacc tgcgacttcc 240tcacaggccc caacacacca agcagcgccg tgtcccgcct agcgcaggcc ctgctggggg 300ctgaggagtg caaggtggac atcctctact accgcaagga tgcctccagc ttccgctgcc 360tggtagatgt ggtgcccgtg aagaacgagg acggggctgt catcatgttc attctcaact 420tcgaggacct ggcccagctc ctggccaagt gcagcagccg cagcttgtcc cagcgcctgt 480tgtcccagag cttcctgggc tccgagggct ctcatggcag gccaggcgga ccagggccag 540gcacaggcag gggcaagtac aggaccatca gccagatccc acagttcacg ctcaacttcg 600tggagttcaa cttggagaag caccgctcca gctccaccac ggagattgag atcatcgcgc 660cccataaggt ggtggagcgg acacagaacg tcactgagaa ggtcacccag gtcctgtccc 720tgggcgcgga tgtgctgccg gagtacaagc tgcaggcgcc gcgcatccac cgctggacca 780tcctgcacta cagccccttc aaggccgtgt gggactggct catcctgctg ctggtcatct 840acacggctgt cttcacgccc tactcagccg ccttcctgct cagcgatcag gacgaatcac 900ggcgtggggc ctgcagctat acctgcagtc ccctcactgt ggtggatctc atcgtggaca 960tcatgttcgt cgtggacatc gtcatcaact tccgcaccac ctatgtcaac accaatgatg 1020aggtggtcag ccacccccgc cgcatcgccg tccactactt caagggctgg ttcctcattg 1080acatggtggc cgccatccct ttcgacctcc tgatcttccg cactggctcc gatgagacca 1140caaccctgat tgggctattg aagacagcgc ggctgctgcg gctggtgcgc gtagcacgga 1200agctggaccg ctactctgag tatggggcgg ctgtgctctt cttgctcatg tgcaccttcg 1260cgctcatagc gcactggctg gcctgcatct gcagcctcac cagcgtgggc ttcggcaatg 1320tctcgcccaa caccaactcc gagaaggtct tctccatctg cgtcatgctc atcggctccc 1380tgatgtacgc cagcatcttc gggaacgtgt ccgcgatcat ccagcgcctg tactcgggca 1440ccgcgcgcta ccacacgcag atgctgcgtg tcaaggagtt catccgcttc caccagatcc 1500ccaacccact gcgccagcgc ctggaggagt atttccagca cgcctggtcc tacaccaatg 1560gcattgacat gaacgcggtg ctgaagggct tccccgagtg cctgcaggct gacatctgcc 1620tgcacctgca ccgcgcactg ctgcagcact gcccagcttt cagcggcgcc ggcaagggct 1680gcctgcgcgc gctagccgtc aagttcaaga ccacccacgc gccgcctggg gacacgctgg 1740tgcacctcgg cgacgtgctc tccaccctct acttcatctc ccgaggctcc atcgagatcc 1800tgcgcgacga cgtggtcgtg gccatcctag gaaagaatga catctttggg gaacccgtca 1860gcctccatgc ccagccaggc aagtccagtg cagacgtgcg ggctctgacc tactgcgacc 1920tgcacaagat ccagcgggca gatctgctgg aggtgctgga catgtacccg gcctttgcgg 1980agagcttctg gagtaagctg gaggtcacct tcaacctgcg ggacgcagcc gggggtctcc 2040actcatcccc ccgacaggct cctggcagcc aagaccacca aggtttcttt ctcagtgaca 2100accagtcaga tgcagcccct cccctgagca tctcagatgc atctggcctc tggcctgagc 2160tactgcagga aatgccccca aggcacagcc cccaaagccc tcaggaagac ccagattgct 2220ggcctctgaa gctgggctcc aggctagagc agctccaggc ccagatgaac aggctggagt 2280cccgcgtgtc ctcagacctc agccgcatct tgcagctcct ccagaagccc atgccccagg 2340gccacgccag ctacattctg gaagcccctg cctccaatga cctggccttg gttcctatag 2400cctcggagac gacgagtcca gggcccaggc tgccccaggg ctttctgcct cctgcacaga 2460ccccaagcta tggagacttg gatgactgta gtccaaagca caggaactcc tcccccagga 2520tgcctcacct ggctgtggca atggacaaaa ctctggcacc atcctcagaa caggaacagc 2580ctgaggggct ctggccaccc ctagcctcac ctctacatcc cctggaagta caaggactca 2640tctgtggtcc ctgcttctcc tccctccctg aacaccttgg ctctgttccc aagcagctgg 2700acttccagag acatggctca gatcctggat ttgcagggag ttggggccac tgaactccaa 2760gataaagaca ccatgaggg 2779 54 2430 DNA Homo sapiens misc_feature IncyteID No 2522075CB1 54 atggccgagg ccgcggagcc ggagggggtt gccccgggtccccaggggcc gccggaggtc 60 cccgcgcctc tggctgagag acccggagag ccaggagccgcgggcgggga ggcagaaggg 120 ccggagggga gcgagggcgc agaggaggcg ccgaggggcgccgccgctgt gaaggaggca 180 ggaggcggcg ggccagacag gggcccggag gccgaggcgcggggcacgag gggggcgcac 240 ggcgagactg aggccgagga gggagccccg gagggtgccgaggtgcccca aggaggggag 300 gagacaagcg gcgcgcagca ggtggagggg gcgagcccgggacgcggcgc gcagggcgag 360 ccccgcgggg aggctcagag ggagcccgag gactctgcggcccccgagag gcaggaggag 420 gcggagcaga ggcctgaggt cccggaaggt agcgcgtccggggaggcggg ggacagcgta 480 gacgcggagg gcccgctggg ggacaacata gaagcggagggcccggcggg cgacagcgta 540 gaggcggagg gccgggtggg ggacagcgta gacgcggaaggtccggcggg ggacagcgta 600 gacgcggagg gcccgctggg ggacaacata caagccgagggcccggcggg ggacagcgta 660 gacgcggagg gccgggtggg ggacagcgta gacgcggaaggtccggcggg ggacagcgta 720 gacgcggagg gccgggtggg ggacagcgta gaggcgggggacccggcggg ggacggcgta 780 gaagcggggg tcccggcggg ggacagcgta gaagccgaaggcccggcggg ggacagcatg 840 gacgccgagg gtccggcagg aagggcgcgc cgggtctcgggtgagccgca gcaatcgggg 900 gacggcagcc tctcgcccca ggccgaggca attgaggtcgcagccgggga gagtgcgggg 960 cgcagccccg gtgagctcgc ctgggacgca gcggaggaggcggaggtccc gggggtaaag 1020 gggtccgaag aagcggcccc cggggacgca agggcagacgctggcgagga cagggtaggg 1080 gatgggccac agcaggagcc gggggaggac gaagagagacgagagcggag cccggagggg 1140 ccaagggagg aggaagcagc ggggggcgaa gaggaatcccccgacagcag cccacatggg 1200 gaggcctcca ggggcgccgc ggagcctgag gcccagctcagcaaccacct ggccgaggag 1260 ggccccgccg agggtagcgg cgaggccgcg cgcgtgaacggccgccggga ggacggagag 1320 gcgtccgagc cccgggccct ggggcaggag cacgacatcaccctcttcgt caaggctggt 1380 tatgatggtg agagtatcgg aaattgcccg ttttctcagcgtctctttat gattctctgg 1440 ctgaaaggcg ttatatttaa tgtgaccaca gtggacctgaaaaggaaacc cgcagacctg 1500 cagaacctgg ctcccggaac aaaccctcct ttcatgacttttgatggtga agtcaagacg 1560 gatgtgaata agatcgagga gttcttagag gagaaattagctcccccgag gtatcccaag 1620 ctggggaccc aacatcccga atctaattcc gcaggaaatgacgtgtttgc caaattctca 1680 gcgtttataa aaaacacgaa gaaggatgca aatgagattcatgaaaagaa cctgctgaag 1740 gccctgagga agctggataa ttacttaaat agccctctgcctgatgaaat agatgcctac 1800 agcaccgagg atgtcactgt ttctggaagg aagtttctgggtggggacga gctgacgctg 1860 gctgactgca acctcttacc caagctccat attattaagattgtggccaa gaagtacaga 1920 gattttgaat ttccttctga aatgactggc atctggagatacttgaataa tgcttatgct 1980 agagatgagt tcacaaatac gtgtccagct gatcaagagattgaacacgc atattcagat 2040 gttgcaaaaa gaatgaaatg aagctgggct gttttctgtcttatttctca gttgagtgag 2100 caaggatacg aaaacagtgt gtttgaaaac aaattaggtttgggttcaat tccttcaatt 2160 tttaaaaaac tggtctctga gagtttttta aatcattgagagcctgtttt tcttctctaa 2220 aacattagtt taattttctt caaaatgaaa atactgctttgtaattacaa aatgagacac 2280 acctatcttg atattttaaa gcaatatcag agggtgtaaagaaggacatt ttaacaatcg 2340 ccttcaattt tactccactt aattaccgaa aacttactggagaacatgtt ccaaatcttc 2400 agtatcttgt tctctctctc tctctctctc 2430

What is claimed is:
 1. An isolated polypeptide selected from the groupconsisting of: a) a polypeptide comprising an amino acid sequenceselected from the group consisting of SEQ ID NO: 1-27, b) a naturallyoccurring polypeptide comprising an amino acid sequence at least 90%identical to an amino acid sequence selected from the group consistingof SEQ ID NO: 1-27, c) a biologically active fragment of a polypeptidehaving an amino acid sequence selected from the group consisting of SEQID NO: 1-27, and d) an immunogenic fragment of a polypeptide having anamino acid sequence selected from the group consisting of SEQ ID NO:1-27.
 2. An isolated polypeptide of claim 1 selected from the groupconsisting of SEQ ID NO: 1-27.
 3. An isolated polynucleotide encoding apolypeptide of claim
 1. 4. An isolated polynucleotide encoding apolypeptide of claim
 2. 5. An isolated polynucleotide of claim 4selected from the group consisting of SEQ ID NO: 28-54.
 6. A recombinantpolynucleotide comprising a promoter sequence operably linked to apolynucleotide of claim
 3. 7. A cell transformed with a recombinantpolynucleotide of claim
 6. 8. A transgenic organism comprising arecombinant polynucleotide of claim
 6. 9. A method for producing apolypeptide of claim 1, the method comprising: a) culturing a cell underconditions suitable for expression of the polypeptide, wherein said cellis transformed with a recombinant polynucleotide, and said recombinantpolynucleotide comprises a promoter sequence operably linked to apolynucleotide encoding the polypeptide of claim 1, and b) recoveringthe polypeptide so expressed.
 10. An isolated antibody whichspecifically binds to a polypeptide of claim
 1. 11. An isolatedpolynucleotide selected from the group consisting of: a) apolynucleotide comprising a polynucleotide sequence selected from thegroup consisting of SEQ ID NO: 28-54, b) a naturally occurringpolynucleotide comprising a polynucleotide sequence at least 90%identical to a polynucleotide sequence selected from the groupconsisting of SEQ ID NO: 28-54, c) a polynucleotide complementary to apolynucleotide of a), d) a polynucleotide complementary to apolynucleotide of b), and e) an RNA equivalent of a)-d).
 12. An isolatedpolynucleotide comprising at least 60 contiguous nucleotides of apolynucleotide of claim
 11. 13. A method for detecting a targetpolynucleotide in a sample, said target polynucleotide having a sequenceof a polynucleotide of claim 11, the method comprising: a) hybridizingthe sample with a probe comprising at least 20 contiguous nucleotidescomprising a sequence complementary to said target polynucleotide in thesample, and which probe specifically hybridizes to said targetpolynucleotide, under conditions whereby a hybridization complex isformed between said probe and said target polynucleotide or fragmentsthereof, and b) detecting the presence or absence of said hybridizationcomplex, and, optionally if present, the amount thereof.
 14. A method ofclaim 13, wherein the probe comprises at least 60 contiguousnucleotides.
 15. A method for detecting a target polynucleotide in asample, said target polynucleotide having a sequence of a polynucleotideof claim 11, the method comprising: a) amplifying said targetpolynucleotide or fragment thereof using polymerase chain reactionamplification, and b) detecting the presence or absence of saidamplified target polynucleotide or fragment thereof, and, optionally, ifpresent, the amount thereof.
 16. A composition comprising a polypeptideof claim 1 and a pharmaceutically acceptable excipient.
 17. Acomposition of claim 16, wherein the polypeptide has an amino acidsequence selected from the group consisting of SEQ ID NO: 1-27.
 18. Amethod for treating a disease or condition associated with decreasedexpression of functional TRICH, comprising administering to a patient inneed of such treatment the composition of claim
 16. 19. A method forscreening a compound for effectiveness as an agonist of a polypeptide ofclaim 1, the method comprising: a) exposing a sample comprising apolypeptide of claim 1 to a compound, and b) detecting agonist activityin the sample.
 20. A composition comprising an agonist compoundidentified by a method of claim 19 and a pharmaceutically acceptableexcipient.
 21. A method for treating a disease or condition associatedwith decreased expression of functional TRICH, comprising administeringto a patient in need of such treatment a composition of claim
 20. 22. Amethod for screening a compound for effectiveness as an antagonist of apolypeptide of claim 1, the method comprising: a) exposing a samplecomprising a polypeptide of claim 1 to a compound, and b) detectingantagonist activity in the sample.
 23. A composition comprising anantagonist compound identified by a method of claim 22 and apharmaceutically acceptable excipient.
 24. A method for treating adisease or condition associated with overexpression of functional TRICH,comprising administering to a patient in need of such treatment acomposition of claim
 23. 25. A method of screening for a compound thatspecifically binds to the polypeptide of claim 1, said method comprisingthe steps of: a) combining the polypeptide of claim 1 with at least onetest compound under suitable conditions, and b) detecting binding of thepolypeptide of claim 1 to the test compound, thereby identifying acompound that specifically binds to the polypeptide of claim
 1. 26. Amethod of screening for a compound that modulates the activity of thepolypeptide of claim 1, said method comprising: a) combining thepolypeptide of claim 1 with at least one test compound under conditionspermissive for the activity of the polypeptide of claim 1, b) assessingthe activity of the polypeptide of claim 1 in the presence of the testcompound, and c) comparing the activity of the polypeptide of claim 1 inthe presence of the test compound with the activity of the polypeptideof claim 1 in the absence of the test compound, wherein a change in theactivity of the polypeptide of claim 1 in the presence of the testcompound is indicative of a compound that modulates the activity of thepolypeptide of claim
 1. 27. A method for screening a compound foreffectiveness in altering expression of a target polynucleotide, whereinsaid target polynucleotide comprises a sequence of claim 5, the methodcomprising: a) exposing a sample comprising the target polynucleotide toa compound, under conditions suitable for the expression of the targetpolynucleotide, b) detecting altered expression of the targetpolynucleotide, and c) comparing the expression of the targetpolynucleotide in the presence of varying amounts of the compound and inthe absence of the compound.
 28. A method for assessing toxicity of atest compound, said method comprising: a) treating a biological samplecontaining nucleic acids with the test compound; b) hybridizing thenucleic acids of the treated biological sample with a probe comprisingat least 20 contiguous nucleotides of a polynucleotide of claim 11 underconditions whereby a specific hybridization complex is formed betweensaid probe and a target polynucleotide in the biological sample, saidtarget polynucleotide comprising a polynucleotide sequence of apolynucleotide of claim 11 or fragment thereof; c) quantifying theamount of hybridization complex; and d) comparing the amount ofhybridization complex in the treated biological sample with the amountof hybridization complex in an untreated biological sample, wherein adifference in the amount of hybridization complex in the treatedbiological sample is indicative of toxicity of the test compound.
 29. Adiagnostic test for a condition or disease associated with theexpression of TRICH in a biological sample comprising the steps of: a)combining the biological sample with an antibody of claim 10, underconditions suitable for the antibody to bind the polypeptide and form anantibody:polypeptide complex; and b) detecting the complex, wherein thepresence of the complex correlates with the presence of the polypeptidein the biological sample.
 30. The antibody of claim 10, wherein theantibody is: a) a chimeric antibody, b) a single chain antibody, c) aFab fragment, d) a F(ab′)₂ fragment, or e) a humanized antibody.
 31. Acomposition comprising an antibody of claim 10 and an acceptableexcipient.
 32. A method of diagnosing a condition or disease associatedwith the expression of TRICH in a subject, comprising administering tosaid subject an effective amount of the composition of claim
 31. 33. Acomposition of claim 31, wherein the antibody is labeled.
 34. A methodof diagnosing a condition or disease associated with the expression ofTRICH in a subject, comprising administering to said subject aneffective amount of the composition of claim
 33. 35. A method ofpreparing a polyclonal antibody with the specificity of the antibody ofclaim 10 comprising: a) immunizing an animal with a polypeptide havingan amino acid sequence selected from the group consisting of SEQ ID NO:1-27, or an immunogenic fragment thereof, under conditions to elicit anantibody response; b) isolating antibodies from said animal; and c)screening the isolated antibodies with the polypeptide, therebyidentifying a polyclonal antibody which binds specifically to apolypeptide having an amino acid sequence selected from the groupconsisting of SEQ ID NO: 1-27.
 36. An antibody produced by a method ofclaim
 35. 37. A composition comprising the antibody of claim 36 and asuitable carrier.
 38. A method of making a monoclonal antibody with thespecificity of the antibody of claim 10 comprising: a) immunizing ananimal with a polypeptide having an amino acid sequence selected fromthe group consisting of SEQ ID NO: 1-27, or an immunogenic fragmentthereof, under conditions to elicit an antibody response; b) isolatingantibody producing cells from the animal; c) fusing the antibodyproducing cells with immortalized cells to form monoclonalantibody-producing hybridoma cells; d) culturing the hybridoma cells;and e) isolating from the culture monoclonal antibody which bindsspecifically to a polypeptide having an amino acid sequence selectedfrom the group consisting of SEQ ID NO: 1-27.
 39. A monoclonal antibodyproduced by a method of claim
 38. 40. A composition comprising theantibody of claim 39 and a suitable carrier.
 41. The antibody of claim10, wherein the antibody is produced by screening a Fab expressionlibrary.
 42. The antibody of claim 10, wherein the antibody is producedby screening a recombinant immunoglobulin library.
 43. A method fordetecting a polypeptide having an amino acid sequence selected from thegroup consisting of SEQ ID NO: 1-27 in a sample, comprising the stepsof: a) incubating the antibody of claim 10 with a sample underconditions to allow specific binding of the antibody and thepolypeptide; and b) detecting specific binding, wherein specific bindingindicates the presence of a polypeptide having an amino acid sequenceselected from the group consisting of SEQ ID NO: 1-27 in the sample. 44.A method of purifying a polypeptide having an amino acid sequenceselected from the group consisting of SEQ ID NO: 1-27 from a sample, themethod comprising: a) incubating the antibody of claim 10 with a sampleunder conditions to allow specific binding of the antibody and thepolypeptide; and b) separating the antibody from the sample andobtaining the purified polypeptide having an amino acid sequenceselected from the group consisting of SEQ ID NO: 1-27.
 45. A polypeptideof claim 1, comprising the amino acid sequence of SEQ ID NO:
 1. 46. Apolypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:2.
 47. A polypeptide of claim 1, comprising the amino acid sequence ofSEQ ID NO:
 3. 48. A polypeptide of claim 1, comprising the amino acidsequence of SEQ ID NO:
 4. 49. A polypeptide of claim 1, comprising theamino acid sequence of SEQ ID NO:
 5. 50. A polypeptide of claim 1,comprising the amino acid sequence of SEQ ID NO:
 6. 51. A polypeptide ofclaim 1, comprising the amino acid sequence of SEQ ID NO:
 7. 52. Apolypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:8.
 53. A polypeptide of claim 1, comprising the amino acid sequence ofSEQ ID NO:
 9. 54. A polypeptide of claim 1, comprising the amino acidsequence of SEQ ID NO:
 10. 55. A polypeptide of claim 1, comprising theamino acid sequence of SEQ ID NO:
 11. 56. A polypeptide of claim 1,comprising the amino acid sequence of SEQ ID NO:
 12. 57. A polypeptideof claim 1, comprising the amino acid sequence of SEQ ID NO:
 13. 58. Apolypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:14.
 59. A polypeptide of claim 1, comprising the amino acid sequence ofSEQ ID NO:
 15. 60. A polypeptide of claim 1, comprising the amino acidsequence of SEQ ID NO:
 16. 61. A polypeptide of claim 1, comprising theamino acid sequence of SEQ ID NO:
 17. 62. A polypeptide of claim 1,comprising the amino acid sequence of SEQ ID NO:
 18. 63. A polypeptideof claim 1, comprising the amino acid sequence of SEQ ID NO:
 19. 64. Apolypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:20.
 65. A polypeptide of claim 1, comprising the amino acid sequence ofSEQ ID NO:
 21. 66. A polypeptide of claim 1, comprising the amino acidsequence of SEQ ID NO:
 22. 67. A polypeptide of claim 1, comprising theamino acid sequence of SEQ ID NO:
 23. 68. A polypeptide of claim 1,comprising the amino acid sequence of SEQ ID NO:
 24. 69. A polypeptideof claim 1, comprising the amino acid sequence of SEQ ID NO:
 25. 70. Apolypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:26.
 71. A polypeptide of claim 1, comprising the amino acid sequence ofSEQ ID NO:
 27. 72. A polynucleotide of claim 11, comprising thepolynucleotide sequence of SEQ ID NO:
 28. 73. A polynucleotide of claim11, comprising the polynucleotide sequence of SEQ ID NO:
 29. 74. Apolynucleotide of claim 11, comprising the polynucleotide sequence ofSEQ ID NO:
 30. 75. A polynucleotide of claim 11, comprising thepolynucleotide sequence of SEQ ID NO:
 31. 76. A polynucleotide of claim11, comprising the polynucleotide sequence of SEQ ID NO:
 32. 77. Apolynucleotide of claim 11, comprising the polynucleotide sequence ofSEQ ID NO:
 33. 78. A polynucleotide of claim 11, comprising thepolynucleotide sequence of SEQ ID NO:
 34. 79. A polynucleotide of claim11, comprising the polynucleotide sequence of SEQ ID NO:
 35. 80. Apolynucleotide of claim 11, comprising the polynucleotide sequence ofSEQ ID NO:
 36. 81. A polynucleotide of claim 11, comprising thepolynucleotide sequence of SEQ ID NO:
 37. 82. A polynucleotide of claim11, comprising the polynucleotide sequence of SEQ ID NO:
 38. 83. Apolynucleotide of claim 11, comprising the polynucleotide sequence ofSEQ ID NO:
 39. 84. A polynucleotide of claim 11, comprising thepolynucleotide sequence of SEQ ID NO:
 40. 85. A polynucleotide of claim11, comprising the polynucleotide sequence of SEQ ID NO:
 41. 86. Apolynucleotide of claim 11, comprising the polynucleotide sequence ofSEQ ID NO:
 42. 87. A polynucleotide of claim 11, comprising thepolynucleotide sequence of SEQ ID NO:
 43. 88. A polynucleotide of claim11, comprising the polynucleotide sequence of SEQ ID NO:
 44. 89. Apolynucleotide of claim 11, comprising the polynucleotide sequence ofSEQ ID NO:
 45. 90. A polynucleotide of claim 11, comprising thepolynucleotide sequence of SEQ ID NO:
 46. 91. A polynucleotide of claim11, comprising the polynucleotide sequence of SEQ ID NO:
 47. 92. Apolynucleotide of claim 11, comprising the polynucleotide sequence ofSEQ ID NO:
 48. 93. A polynucleotide of claim 11, comprising thepolynucleotide sequence of SEQ ID NO:
 49. 94. A polynucleotide of claim11, comprising the polynucleotide sequence of SEQ ID NO:
 50. 95. Apolynucleotide of claim 11, comprising the polynucleotide sequence ofSEQ ID NO:
 51. 96. A polynucleotide of claim 11, comprising thepolynucleotide sequence of SEQ ID NO:
 52. 97. A polynucleotide of claim11, comprising the polynucleotide sequence of SEQ ID NO:
 53. 98. Apolynucleotide of claim 11, comprising the polynucleotide sequence ofSEQ ID NO: 54.